Il-2alpha receptor subunit binding compounds

ABSTRACT

Peptidyl IL-2Rα ligands and compounds comprising the IL-2Rα ligands are disclosed. The IL-2Rα ligands and compounds such as synthetic monomers, homodimers, or heteromers and recombinant fusion proteins comprising the IL-2Rα ligands can be used as targeting or imaging agents, as diagnostics or to treat cancers and autoimmune diseases.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/856,305 filed on Jun. 3, 2019, which isincorporated by reference in its entirety.

FIELD

The present disclosure relates to peptidyl IL-2Rα ligands and tocompounds having a peptidyl IL-2Rα ligand. Compounds such as syntheticmonomers, homodimers, heteromers, and recombinant fusion proteinscomprising the IL-2Rα ligands can be used as targeting agents, imagingagents, diagnostic agents, and as therapeutics to treat cancer andautoimmune diseases.

SEQUENCE LISTING

The Sequence Listing associated with this application is filed inelectronic format via EFS-Web and is incorporated by reference in itsentirety. Said ASCII copy, created on Jul. 28, 2020, is named62AJ-000210US-309981_SL.txt and is 200,417 bytes in size.

BACKGROUND

Interleukin-2 (IL-2) plays a crucial role in regulating immune responsesand maintaining peripheral self-tolerance by having bothimmuno-stimulatory and immuno-regulatory functions. IL-2 acts primarilyas a T cell growth factor and is essential for The proliferation andsurvival of T cells as well as the generation of effector and memory Tcells. IL-2 is a four α-helical bundle cytokine that belongs to a familyof structurally related cytokines that includes IL-4, IL-7, IL-9, IL-15,and IL-21. IL-2 is produced by activated CD4⁺ T cells in response toantigen stimulation and can also be produced by CD8⁺ T cells and innateimmune cells such as activated dendritic cells (DCs) and natural killer(NK) cells.

IL-2 binds to various forms of the IL-2 receptor (IL-2R), notably themonomeric, dimeric, and trimeric forms. Monomeric IL-2R consists of themembrane-associated IL-2Rα (CD25) chain, which also exists in a solubleform; however, it is not capable of inducing signaling events. Thetrimeric IL-2R consists of IL-2Rα, IL2-Rβ (CD122), and IL-2Rγ, alsoknown as the common γ-chain (γc) or CD132 and is shared by all membersof the IL-2 cytokine family. Dimeric IL-2R comprises the IL-2Rγc andIL-2Rβ subunits. In contrast to monomeric IL-2R, both the dimeric andtrimeric IL-2 receptors lead to a downstream signaling cascade upon IL-2binding. IL-2 binds with high affinity to the trimeric IL-2R but withlow-moderate affinity to the dimeric IL-2R, varying the sensitivity ofthe cell to IL-2. Additionally, IL-2 can bind to IL-2Rα expressed on thesurface of activated dendritic cells for trans presentation toneighboring cells including antigen-specific naïve T cells and NK cellsthat express both I-2Rβ and IL-2Rγc subunits. This trans presentation ofIL-2 has been shown to facilitate initial high affinity IL-2 signaling,required early in the immune response to prime naïve T-cells to produceIL-2.

TL-2 is first captured by IL-2Rα, bringing about a conformational changeto IL-2, increasing its affinity for IL-2Rβ. Association of IL-2 withthe IL-2Rαγc subunits induces the dimerization of the signaling motifsin the cytoplasmic tails of IL-2Rβ and IL-2Rγc leading to thephosphorylation/activation of the Janus kinases, JAK1 and JAK3, which inturn exert kinase activity on key tyrosine residues in the tail of theIL-2Rβ subunit.

Downstream signaling occurs via three major pathways, the JAK-STATpathway, the phosphoinositide 3-kinase (PI3K)-AKT pathway, and themitogen-activated protein kinase (MAPK) pathway. These pathwaysultimately result in the transcription of target genes that contributeto IL-2-dependent biological actions, through the recruitment of theadaptor protein She and the transcription factor STAT5. Target genes ofTL-2 signaling include cyclin D2, bcl-2, fasI, cd25 (encoding IL-2Rα),socs1-2, and the IL-2 silencing gene prdm1, which encodes for thetranscription factor, BLIMP. The production of the negative regulator ofIL-2 BLIMP1 is essential for maintaining the balance between effector Tcells and Treg cells, which is crucial for immune homeostasis.

IL-2 plays a dual role in T cell activation by stimulating theproliferation and differentiation or T cells as well as by maintainingand expanding the population of immuno-suppressive Treg cells. Theconventional naïve CD4+ and CD8+ T cells express the dimeric TL-2R, andtherefore require a high concentration of IL-2 to induce their initialproliferation. Once activated, these T cells express the high-affinitytrimeric IL-2R, driving the differentiation of the cells into eithereffector (Teff) or memory cells. This differentiation depends on thestrength and duration of the IL-2 signal.

During the primary expansion of CD8⁺ T cells due to low-moderate levelsof IL-2, a subset of CD8⁺ T cells will differentiate into memory Tcells. They do this by downregulating CD25 and upregulating CD127(IL-7R) and CD62 (L-selectin), which are crucial receptors for secondaryresponses upon re-infection. During an acute infection, sustained highlevels of IL-2 leads to a rapid up-regulation of CD25, and thedifferentiation of CD8+ cells into cytotoxic effector cells. Theupregulation induces an IL-2 driven expression of the death receptor fasand fasL, causing activation-induced cell death (AICD) upon pathogenclearance. For CD4⁺ T cells, the activation of STAT5 signaling by IL-2influences their differentiation into multiple helper T cellpopulations, including Th1, Th2, and Th17 by regulating the expressionof the appropriate receptors for each response.

Homeostatic or background levels of IL-2 are essential for the survivaland function of Treg cells by maintaining the expression of FOXP3 andCD25. Treg cells naturally occur in the thymus and upon contact withself-peptides become activated. Additionally, Treg cells can begenerated by stimulation of conventional CD4⁺ T cells upon interactionwith antigens in peripheral lymphoid organs. Because Treg cells do notproduce IL-2, Treg cells are dependent on IL-2 producing cells such asconventional T cells. Additionally, due to the high expression of IL-2Rα(CD25) Treg cells are able to consume and limit the systemicconcentration of IL-2, ensuring the regulation of the immune balance. Inthe absence of IL-2, the number of Treg cells decreases and the numberof effector T cells increases, leading to an enhanced susceptibility toautoimmune and inflammatory disorders. Therefore, the unique activationof Treg cells at low levels of IL-2, which does not activate CD4⁺ orCD8⁺ T cells, has allowed for the development of IL-2 as a therapeuticin autoimmune and inflammatory diseases.

The production of IL-2 from both arms of the immune system highlightsthe importance of IL-2 in the early stages of infection, as well as thesecondary adaptive response. Furthermore, the dual functions of IL-2 inboth protective immunity and in immune tolerance allows IL-2 to be apotential therapeutic as both an immune stimulant for cancer treatmentand as an immune suppressor for the treatment of autoimmune disease.

SUMMARY

According to the present invention, IL-2Rα ligands bind to the humanIL-2Rα subunit with an IC₅₀ of less than 100 μM.

According to the present invention, compounds comprise an IL-2Rα ligandaccording to the present invention.

According to the present invention, pharmaceutical compositions comprisean IL-2Rα ligand according to the present invention; a compoundaccording to the present invention; or a combination of any of theforegoing.

According to the present invention, methods of treating cancer in apatient, comprise administering to a patient in need of such treatment atherapeutically effective amount of a pharmaceutical compositionaccording to the present invention.

According to the present invention, methods of treating an autoimmunedisease in a patient, comprise administering to a patient in need ofsuch treatment, a therapeutically effective amount of a pharmaceuticalcomposition according to the present invention.

According to the present invention, methods of screening compounds forIL-2α activity, comprise contacting a cell with an IL-2Rα ligandaccording to the present invention; the compound according to thepresent invention; or a combination of any of any of the foregoingwherein the cell expresses an IL-2α subunit; and contacting the cellwith a test compound; and determining the activity of the test compound.

According to the present invention, methods of treating a disease in apatient, wherein the IL-2 receptor signaling pathway is associated withthe etiology of the disease, comprise administering to a patient in needof such treatment a therapeutically effective amount of a compoundcomprising an IL-2Rα ligand according to the present invention, or apharmaceutical composition thereof.

According to the present invention, methods of treating a disease in apatient, wherein activating the IL-2 receptor is effective in treatingthe disease, comprise administering to a patient in need of suchtreatment a therapeutically effective amount of a compound comprising anIL-2Rα ligand according to the present invention or a pharmaceuticalcomposition thereof.

According to the present invention, methods of treating a disease in apatient, wherein inhibiting the IL-2 receptor is effective in treatingthe disease, comprise administering to a patient in need of suchtreatment a therapeutically effective amount of a compound comprising anIL-2Rα ligand according to the present invention or a pharmaceuticalcomposition thereof.

According to the present invention, methods of treating a disease in apatient, wherein modulating the activity of the IL-2Rα subunit iseffective in treating the disease, comprise administering to a patientin need of such treatment a therapeutically effective amount of acompound comprising an IL-2Rα ligand according to the present inventionor a pharmaceutical composition thereof.

According to the present invention, methods of treating a disease in apatient, wherein inhibiting binding to the IL-2Rα subunit is effectivein treating the disease, comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of a compoundcomprising an IL-2Rα ligand according to the present invention or apharmaceutical composition thereof.

According to the present invention, methods of treating a disease in apatient, wherein the etiology of the disease is associated withactivation of Treg cells, comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of a compoundcomprising an IL-2Rα ligand according to the present invention or apharmaceutical composition thereof.

According to the present invention, methods of treating a disease in apatient, wherein the etiology of the disease is associated with cellsexhibiting a high IL-2Rα expression, comprise administering to a patientin need of such treatment a therapeutically effective amount of acompound comprising an IL-2Rα ligand according to the present inventionor a pharmaceutical composition thereof.

According to the present invention, methods of imaging cells expressingthe IL-2Rα subunit comprise administering to a patient an effectiveamount of a compound comprising an IL-2Rα ligand according to thepresent invention.

According to the present invention, methods of diagnosing a disease in apatient wherein the disease is associated with cells expressing theIL-2Rα subunit comprise administering to a patient an effective amountof a compound comprising an IL-2Rα ligand according to the presentinvention.

According to the present invention, methods of targeting a compound tocells expressing the IL-2Rα subunit comprise administering to a patientan effective amount of a compound comprising an IL-2Rα ligand accordingto the present invention.

According to the present invention, methods of delivering a cytotoxiccompound to cells expressing the IL-2Rα subunit comprise administeringto a patient an effective amount of a compound comprising a cytotoxicmoiety and an IL-2Rα ligand according to the present invention.

DETAILED DESCRIPTION

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—X¹—X²— denotes amino acids X¹ and X² covalently bonded through a singlebond.

“Affinity” refers to strength of the binding interaction between asingle biomolecule to its ligand/binding partner. Affinity is expressedas the IC₅₀.

“Agonist” refers to a biologically active ligand or compound that bindsto its complementary biologically active receptor or subunit andactivates the receptor to cause a biological response mediated by thereceptor, or to enhance a preexisting biological activity mediated bythe receptor.

“Partial agonist” refers to a compound that provides a level ofactivation, that is, for example, less than 75% of maximum activation,less than 50%, less than 25%, less than 10%, or less than 1% of themaximum activation. A partial IL-2R agonist exhibits a level ofactivation that is less than the level of activation provided by IL-2.

“Antagonist” refers to a biologically active ligand or compound thatbinds to its complementary receptor or subunit and blocks or reduces abiological response of the receptor.

Amino acid residues are abbreviated as follows: alanine is Ala or A;arginine is Arg is R; asparagine is Asn or N; aspartic acid is Asp or D;cysteine is Cys or C; glutamic acid is Glu or E; glutamine is Gln or Q;glycine is Gly or G; histidine is His or H; isoleucine is Ile or I;leucine is Leu or L; lysine is Lys or K; methionine is Met or M;phenylalanine is Phe or F; proline is Pro or P; serine is Ser or S;threonine is Thr or T; tryptophan is Trp or W; tyrosine is Tyr or Y; andvaline is Val or V.

“Non-natural amino acids” include, for example, β-amino acids,homo-amino acids, proline and pyruvic acid derivatives, histidinederivatives with alkyl or heteroatom moieties attached to the imidazolering, amino acids with pyridine-containing side chains, 3-substitutedalanine derivatives, glycine derivatives, ring-substituted phenylalanineand tyrosine derivatives, and N-methyl amino acids.

Amino acids having a large hydrophobic side chain include isoleucine(I), leucine (L), methionine (M), valine (V), phenylalanine (F),tyrosine (Y), and tryptophan (W).

Amino acids having a small hydrophobic side chain include alanine (A),glycine (G), proline (P), serine (S), and threonine (T).

Amino acids having a basic side chain include arginine (R), lysine (K),and histidine (H).

Amino acids having an acidic side chain include aspartate (D) andglutamate (E).

Amino acids having a polar/neutral side chain include histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), and tyrosine(Y).

Amino acids having an aromatic side chain include phenylalanine (F),histidine (H), tryptophan (W), and tyrosine (Y).

Amino acids having a hydroxyl side chain include serine (S), threonine(T), or tyrosine (Y).

“Conservative amino acid substitution” means that amino acids withineach of the following groups can be substituted with another amino acidwithin the group: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), and tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) and glutamate (E);amino acids comprising a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), andtyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), and histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), andtryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), and tyrosine (Y).

“Expression” as used herein generally refers to expression of constructsuch as an IL-2 receptor or the outer surface of a cell.

Molecular weight refers to the number average molecular weight asdetermined by gel permeation chromatography using a polystyrenestandard.

A linker refers to a moiety that binds at least one IL-2R ligand such asan IL-2Rα ligand, an IL-2Rβ ligand, and/or an IL-2Rγc ligand. A linkercan bind to another IL-2R ligand which can be the same IL-2R ligand or adifferent IL-2R ligand. A linker can also bind to one or more additionalmoieties and/or compounds that can provide a desired physiologicalfunction. A linker can be divalent or multivalent. A linker can behydrolytically stable or may be cleavable such as a physiologicallyhydrolyzable or enzymatically degradable linkage. A linker can bindIL-2R ligands to form dimers, trimers, or higher order multi-ligandpeptides (heteromers) and compounds.

A “physiologically cleavable” or “hydrolyzable” or “degradable” bondrefers to a bond that reacts with water (i.e., is hydrolyzed) underphysiological conditions. The tendency of a bond to hydrolyze in waterwill depend not only on the general type of linkage connecting twocentral atoms but also on the substituents attached to these centralatoms. Suitable hydrolytically unstable or weak linkages include but arenot limited to carboxylate ester, phosphate ester, anhydrides, acetals,ketals, acyloxyalkyl ether, imines, orthoesters, peptides andoligonucleotides.

An “enzymatically degradable linkage” refers to a linkage that can bedegraded or cleaved by one or more enzymes.

A “hydrolytically stable” linkage or bond refers to a chemical bond,such as a covalent bond, that is substantially stable in water such thatthe chemical bond does not undergo hydrolysis under physiologicalconditions to any appreciable extent over an extended period of time.Examples of hydrolytically stable linkages include, for example,carbon-carbon bonds (e.g., in aliphatic chains), ethers, amides,urethanes, and the like. Generally, a hydrolytically stable linkage isone that exhibits a rate of hydrolysis of less than about 1% to 2% perday under physiological conditions.

An “IL-2Rβ ligand” refers to a peptide capable of binding to the IL-2Rβsubunit of a mammalian IL-2 receptor, such as a human IL-2 receptor,with an affinity (IC₅₀) less than 100 μM. Suitable IL-2Rβ ligands aredisclosed, for example, in U.S. Application Publication No. 2020/0040034A1 and in U.S. Provisional Application No. 62/930,758 filed on Nov. 5,2019, each of which is incorporated by reference in its entirety.

An “IL-2Rγc ligand” refers to a peptide capable of binding to theIL-2Rγc subunit of a mammalian IL-2 receptor, such as a human IL-2receptor, with an affinity (IC₅₀) less than 100 μM. IL-2Rγc ligands aredisclosed in U.S. Application Publication No. 2020/0040036 A1 and inU.S. Provisional Application No. 62/930,758 filed on Nov. 5, 2019, eachof which is incorporated by reference in its entirety.

An “IL-2Rα ligand” refers to a peptide capable of binding to the IL-2Rαsubunit of a mammalian IL-2 receptor, such as a human IL-2 receptor,with an affinity (IC₅₀) less than 100 μM.

The “human IL-2Rβ ligand” refers to a peptide capable of binding to theIL-2Rβ subunit of the human IL-2 receptor with an affinity less than 100μM.

The “human IL-2Rγc ligand” refers to a peptide capable of binding to theIL-2Rγc subunit of a mammalian IL-2 receptor with an affinity (IC₅₀)less than 100 μM.

The “human IL-2Rα ligand” comprises refers to a peptide capable ofbinding to the IL-2Rα subunit of the human IL-2 receptor with anaffinity (IC₅₀) less than 100 μM.

The “human IL-2Rβ subunit” refers to NP_000869.1.

The “human IL-2Rγc subunit” refers to NP_000197.1.

The “human IL-2Rα subunit” refers to NP_001295172.1 and/orNP_001295171.1,

An “IL-2R binding fusion protein” refers to a protein made byrecombinant DNA technology in which the translational reading frame ofan IL-2R ligand is fused to that of another protein (“IL-2R bindingfusion partner”) to produce a single recombinant polypeptide. An IL-2Rfusion protein can comprise an IL-2Rα ligand, an IL-2Rβ ligand, and/oran IL-2Rγc ligand. An IL-2R binding fusion protein can be produced as adisulfide-linked dimer, joined together by disulfide bonds located inthe hinge region. An IL-2R ligand binding fusion protein can include apeptide linker such as an amino acid sequence located between twoproteins comprising a fusion protein, such that the linker peptidesequence is not derived from either partner protein. Peptide linkers canbe incorporated into fusion proteins as spacers to promote properprotein folding and stability of the component protein moieties, toimprove protein expression, or to enable better bioactivity of the twofusion partners.

Bioisosteres are atoms or molecules that fit the broadest definition forisosteres and is used interchangeably with the term isostere. Theconcept of bioisosterism is based on the concept that single atom,groups, moieties, or whole molecules, which have chemical and physicalsimilarities produce similar biological effects. A bioisostere of aparent compound can still be recognized and accepted by its appropriatetarget, but its functions will be altered as compared to the parentmolecule. Parameters affected with bioisosteric replacements include,for example, size, conformation, inductive and mesomeric effects,polarizability, capacity for electrostatic interactions, chargedistribution, H-bond formation capacity, pKa (acidity), solubility,hydrophobicity, lipophilicity, hydrophilicity, polarity, potency,selectivity, reactivity, or chemical and metabolic stability, ADME(absorption, distribution, metabolism, and excretion). Although commonin pharmaceuticals, carboxyl groups or carboxylic acid functional groups(—CO₂H) in a parent molecule may be replaced with a suitable surrogateor (bio)isostere to overcome chemical or biological shortcomings whileretaining the desired attributes of the parent molecule bearing one ormore carboxyl groups or carboxylic acid functional groups (—CO₂H).

“Isostere” or “isostere replacement” refers to any amino acid or otheranalog moiety having physiochemical and/or structural properties similarto a specified amino acid. An “isostere” or “suitable isostere” of anamino acid is another amino acid of the same class, wherein amino acidsbelong to the following classes based on the propensity of the sidechain to be in contact with polar solvent like water: hydrophobic (lowpropensity to be in contact with water), polar or charged (energeticallyfavorable contact with water). Examples of charged amino acid residuesinclude lysine (+), arginine (+), aspartate (−) and glutamate (−).Examples of polar amino acids include serine, threonine, asparagine,glutamine, histidine and tyrosine. Illustrative hydrophobic amino acidsinclude alanine, valine, leucine, isoleucine, proline, phenylalanine,tryptophan, cysteine and methionine. The amino acid glycine does nothave a side chain and is hard to assign to one of the above classes.However, glycine is often found at the surface of proteins, often withinloops, providing high flexibility to these regions, and an isostere mayhave a similar feature. Proline has the opposite effect, providingrigidity to the protein structure by imposing certain torsion angles onthe segment of the polypeptide chain. An isostere can be a derivative ofan amino acid, e.g., a derivative having one or more modified sidechains as compared to the reference amino acid.

“Cyclized” refers to a reaction in which one part of a peptide orpolypeptide molecule becomes linked to another part of the peptide orpolypeptide molecule to form a closed ring, such as by forming adisulfide bridge or other similar bond, e.g., a lactam bond. A peptidemonomer compound or monomer subunit of peptide dimer compounds can becyclized via an intramolecular bond between two amino acid residuespresent in the peptide monomer or monomer subunit.

“Patient” refers to a mammal, for example, a human.

“Peptide” refers to a polymer in which the monomers are α-amino acidsjoined together through amide bonds. A peptide can comprise less than100 amino acids, less than 50 amino acids, less than 40 amino acids,less than 30 amino acids, or less than 20 amino acids. A peptide cancomprise naturally-occurring α-amino acids, non-naturally occurringamino acids, or a combination thereof.

“Polypeptide” refers to a polymer in which the monomers are α-aminoacids joined together through amide bonds and comprise greater than 50amino acids.

“N-terminus” refers to the end of a peptide or polypeptide, such as anN-terminus of a peptide or polypeptide comprising an IL-2Rα ligand, anIL-2Rβ ligand, and/or an IL-2Rγc ligand, that bears an amino group incontrast to the carboxyl end bearing a carboxyl acid group.

“C-terminus” refers to the end of a peptide or polypeptide, such as aC-terminus of a peptide or polypeptide comprising an IL-2Rα ligand, anIL-2Rβ ligand, and/or an IL-2Rγc ligand, that bears a carboxylic acidgroup in contrast to the amino terminus bearing an amino group.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts can be formed with organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like. A salt can be formed when one or more acidic protons presentin the parent compound are replaced by a metal ion, e.g., an alkalimetal ion, an alkaline earth ion, or an aluminum ion, or combinationsthereof; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, and N-methylglucamine. Apharmaceutically acceptable salt can be the hydrochloride salt. Apharmaceutically acceptable salt can be the sodium salt. A compound canhave two or more ionizable groups, a pharmaceutically acceptable saltcomprises one or more counterions, such as a bi-salt, for example, adihydrochloride salt.

“Pharmaceutically acceptable salt” includes hydrates and other solvates,as well as salts in crystalline or non-crystalline form. Where aparticular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt (e.g., a hydrochloride salt) is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,which are known to be innocuous to a patient, e.g., water, ethanol, andthe like. A molecular complex of a compound or moiety of a compound anda solvent can be stabilized by non-covalent intra-molecular forces suchas, for example, electrostatic forces, van der Waals forces, or hydrogenbonds. The term “hydrate” refers to a solvate in which the one or moresolvent molecules is water.

“Pharmaceutical composition” refers to a compound comprising an IL-2Rαligand provided by the present disclosure or a pharmaceuticallyacceptable salt thereof and at least one pharmaceutically acceptablevehicle, with which the compound or pharmaceutically acceptable saltthereof is administered to a patient. Pharmaceutically acceptablevehicles are known in the art.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecompound in a preventative fashion. The application of a therapeutic forpreventing or prevention of a disease of disorder is known asprophylaxis.

“Prodrug” refers to a derivative of a therapeutic compound that requiresa transformation within the body to release the active therapeuticcompound. Prodrugs are frequently, although not necessarily,pharmacologically inactive until converted to the parent drug.“Promoiety” refers to a group bonded to a therapeutic compound,typically to a functional group of the therapeutic compound, via bond(s)that are cleavable under specified conditions of use. The bond(s)between the drug and promoiety may be cleaved by enzymatic ornon-enzymatic means. Under the conditions of use, for example followingadministration to a patient, the bond(s) between the therapeuticcompound and the promoiety may be cleaved to release the parenttherapeutic compound. The cleavage of the promoiety may proceedspontaneously, such as via a hydrolysis reaction, or it may be catalyzedor induced by another agent, such as by an enzyme, by light, by acid, orby a change of or exposure to a physical or environmental parameter,such as a change of temperature or pH. The agent may be endogenous tothe conditions of use, such as an enzyme present in the systemiccirculation of a patient to which the prodrug is administered or theacidic conditions of the stomach or the agent may be suppliedexogenously.

“Substantially” means, for example, greater than 90%, greater than 95%,greater than 98%, or greater than 99%.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a patient for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. A “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, the severity of the diseaseand/or symptoms of the disease or disorder, the age, weight, and/orhealth of the patient to be treated, and the judgment of the prescribingphysician. A therapeutically effective amount in any given instance maybe ascertained by those skilled in the art or capable of determinationby routine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease or at least one of the clinical symptoms of adisease or disorder, reducing the risk of acquiring a disease or atleast one of the clinical symptoms of a disease, reducing thedevelopment of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter or manifestation that may or may not bediscernible to the patient. In certain embodiments, “treating” or“treatment” refers to delaying the onset of the disease or at least oneor more symptoms thereof in a patient who may be exposed to orpredisposed to a disease or disorder even though that patient does notyet experience or display symptoms of the disease.

“Tregs” or “Treg cells” refer to regulatory T-cells. Regulatory T-cellsare a class of T-cells that suppress the activity of other immune cellsand are defined using flow cytometry by the cell marker phenotypesCD4+/CD25+/FOXP3+, CD4+CD25+CD127lo, or CD4+/CD25+/FOXP3+/CD127lo.Because FOXP3 is an intracellular protein and requires cell fixation andpermeabilization for staining, the cell surface phenotypeCD4+CD25+CD127lo− can be used for defining live Tregs. Tregs alsoinclude various Treg subclasses, such as tTregs (thymus-derived) andpTregs (peripherally-derived, differentiated from naive T-cells in theperiphery). All Tregs express the IL-2Rαβγc receptor, do not produceIL-2 and are dependent on IL-2 for growth. Tregs are more potentlyactivated by an IL-2Rαβγc-biased agonist. Treg cells are characterizedby expression of the α-subunit of the IL-2 receptor (CD25) and thetranscription factor forkhead box P3 (FOXP3) and play a critical role inthe induction and maintenance of peripheral self-tolerance to antigens,including those expressed by tumors. Treg cells require IL-2 for theirfunction and development and induction of their suppressivecharacteristics.

“CD4+ T cells” are a type of lymphocyte that functions to coordinate theimmune response by stimulating other immune cells such as macrophages, Blymphocytes (B cells), CD8 lymphocytes (CD8 cells) to fight infection.CD4+ T cells recognize peptides presented on MHC Class II molecules,which are found on antigen-presenting cells.

“CD8+(cytotoxic) T-cells” are generated in the thymus and express theT-cell receptor. Cytotoxic T-cells express a dimeric co-receptor, CD8,which typically comprises one CD8α and one CD8β chain. CD8+ T-cellsrecognize peptides presented by MHC Class 1 molecules found on allnucleated cells. The CD8 heterodimer binds to a conservative portion ofMHC Class 1 during T-cell/antigen presenting cell interactions. CD8+T-cells (cytotoxic T lymphocytes, or CTLs) are important for immunedefense against intracellular pathogens including viruses and bacteria,and for tumor surveillance.

“Functional activation of Treg cells” is defined as an IL-2-mediatedresponse in Tregs. Assays for functional activation of Treg cellsinclude stimulation of pSTAT5, Treg cell proliferation, and stimulationof the levels of Treg effector proteins.

“Polypeptide” refers to a molecule composed of monomers (amino acids)linearly linked by amide bonds (also known as peptide bonds). The term“polypeptide” refers to any chain of two or more amino acids and doesnot refer to a specific length of the product. Thus, peptides,dipeptides, tripeptides, oligopeptides, “protein,” “amino acid chain,”or any other term used to refer to a chain of two or more amino acids,are included within the definition of “polypeptide,” and the term“polypeptide” may be used instead of, or interchangeably with any ofthese terms. The term “polypeptide” is also intended to refer to theproducts of post-expression modifications of the polypeptide including,for example, glycosylation, acetylation, phosphorylation, amidation,derivatization by known protecting/blocking groups, proteolyticcleavage, and/or modification by non-naturally occurring amino acids. Apolypeptide may be derived from a natural biological source or producedby recombinant technology but is not necessarily translated from adesignated nucleic acid sequence. A polypeptide may be generated in anymanner, including by recombinant methods or by chemical synthesis. Apolypeptide may have, for example, more than 100 amino acids, more than200 amino acids, more than 500 amino acids, more than 1,000 amino acids,or more than 2,000 amino acids. Polypeptides may have a definedthree-dimensional structure, although they do not necessarily have suchstructure. Polypeptides with a defined three-dimensional structure arereferred to as folded, and polypeptides which do not possess a definedthree-dimensional structure, but rather can adopt a large number ofdifferent conformations and are referred to as unfolded.

“Polynucleotide” refers to an isolated nucleic acid molecule orconstruct, e.g., messenger RNA (mRNA), virally-derived RNA, or plasmidDNA (pDNA). A polynucleotide may comprise a conventional phosphodiesterbond or a non-conventional bond, such as an amide bond, such as found inpeptide nucleic acids (PNA).

“Nucleic acid molecule” refers to any one or more nucleic acid segments,such as DNA or RNA fragments, present in a polynucleotide.

“Vector” or “expression vector” is synonymous with “expressionconstruct” and refers to a DNA molecule that is used to introduce anddirect the expression of a specific gene to which it is operablyassociated in a target cell. A vector can be a self-replicating nucleicacid structure as well as a vector incorporated into the genome of ahost cell into which it has been introduced. An expression vector cancomprise an expression cassette. Expression vectors allow transcriptionof large amounts of stable mRNA. Once an expression vector is inside thetarget cell, the ribonucleic acid molecule or protein that is encoded bythe gene is produced by the cellular transcription and/or translationmachinery. An expression vector can comprise an expression cassette thatcomprises polynucleotide sequences that encode an IL-2Rβγc ligand orIL-2Rβγc ligand construct provided by the present disclosure.

“Host cell,” “host cell line,” and “host cell culture” refer to cellsinto which are exogenous nucleic acid has been introduced, including theprogeny of such cells. Host cells include, for example, “transformants”and “transformed cells,” which include the primary transformed cell andprogeny derived from the primary transformed cell without regard to thenumber of passages.

“Antibody” in the broadest sense encompasses various antibody structuresincluding, for example, monoclonal antibodies, polyclonal antibodies,multi-specific antibodies such as bispecific antibodies, and antibodyfragments that exhibit a desired antigen binding activity.

“Full-length antibody,” “intact antibody,” and “whole antibody” refer toan antibody having a structure substantially similar to a nativeantibody structure or having heavy chains that contain both Fab and anFc region.

“Antibody fragment” refers to a molecule other than an intact antibodythat comprises a portion of an intact antibody that binds the antigen towhich the intact antibody binds. Examples of antibody fragments includeFv, Fab, Fab′, Fab′-SH, F(ab′)2, diabodies, linear antibodies,single-chain antibody molecules such as scFv, and multi-specificantibodies formed from antibody fragments. Diabodies are antibodyfragments with two antigen binding sites that may be bivalent orbispecific. Antibody fragments can be made by various techniques,including but not limited to proteolytic digestion of an intact antibodyas well as production by recombinant host cells such as E. coli orphage.

“Fab” or “Fab region” refers to a polypeptide that comprises the VH,CHI, VL, and CL immunoglobulin domains, generally on two differentpolypeptide chains such as VH—CH on one chain and VL-CL on the other.Fab may refer to this region in isolation, or this region in the contextof a bispecific antibody. In the context of a Fab, the Fab comprises anFv region in addition to the CHI and CL domains.

“Fv” or “Fv fragment” or “Fv region” refers to a polypeptide thatcomprises the VL and VH domains of an antibody (Fab). Fv regions can beformatted as both Fabs (generally two different polypeptides that alsoinclude the constant regions) and scFvs, where the vi and vh domains arecombined (generally with a linker as discussed) to form an scFv.

“Single chain Fv” or “scFv” refers to a variable heavy domain covalentlyattached to a variable light domain, generally using a scFv linker asdiscussed herein, to form a scFv or scFv domain. A scFv domain can be ineither orientation from N- to C-terminus.

“Effector function” refers to a biochemical event that results from theinteraction of an antibody Fc region with an Fc receptor or ligand.Effector functions include, for example, antibody-dependent cellulartoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), andcomplement-dependent cytotoxicity (CDC).

“Fc” or “Fc region” or “Fc chain” refers to polypeptide comprising theconstant region of an antibody, in some instances, excluding all or aportion of the first constant region immunoglobulin domain (e.g., CHI)or a portion thereof, and in some cases, further excluding all or aportion of the hinge. Thus, an Fc can refer to the last two constantregion immunoglobulin domains (e.g., CH2 and CH3) of IgA, IgD, and IgG,the last three constant region immunoglobulin domains of IgE and IgM,and optionally, all or a portion of the flexible hinge N-terminal tothese domains. For IgA and IgM, Fc may include the J chain. For IgG, theFc chain comprises immunoglobulin domains CH2 and CH3 (Cy2 and Cy3), andoptionally all or a portion of the hinge region between CHI (Cy1) andCH2 (Cy2). Although the boundaries of the Fc region may vary, the humanIgG heavy chain Fc region is usually defined to include residues E216,C226, or A231 to its carboxyl-terminus, wherein the numbering isaccording to the EU index as in Kabat. An amino acid modification can bemade to the Fc region, for example to alter binding to one or more FcyRor to the FcRn. In EU numbering for human IgG1, the CH2-CH3 domaincomprises amino acids 231 to 447, and the hinge is 216 to 230. Thus, thedefinition of Fc chain includes both amino acids 231-447 (CH2-CH3) or216-447 (hinge-CH2-CH3), or fragments thereof. An Fc fragment cancontain fewer amino acids from either or both of the N- and C-terminithat retains the ability to form a dimer with another Fc chain or Fcfragment as can be detected using standard methods, generally based onsize (e.g., non-denaturing chromatography, size exclusionchromatography, etc.). Human IgG Fc chains are of particular use, andcan be the Fc chain from human IgG1, IgG2 or IgG4.

“Heavy constant region” refers to the CH1-hinge-CH2-CH3 portion of anantibody or fragments thereof, excluding the variable heavy domain; inEU numbering of human IgG1, such as amino acids 118-447. “Heavy chainconstant region fragment” refers to a heavy chain constant region thatcontains fewer amino acids from either or both of the N- and C-terminithat retains the ability to form a dimer with another heavy chainconstant region.

“Immunoglobulin molecule” refers to a protein having the structure of anaturally occurring antibody. For example, immunoglobulins of the IgGclass are heterotetrameric glycoproteins of about 150,000 Da, composedof two light chains and two heavy chains that are bonded togetherthrough disulfide bonds. From N- to C-terminus, each heavy chain has avariable region (VH), also called a variable heavy domain or a heavychain variable domain, followed by three constant domains (CHI, CH2, andCH3), also called a heavy chain constant region. Similarly, from N- toC-terminus, each light chain has a variable region (VL), also called avariable light domain or a light chain variable domain, followed by aconstant light (CL) domain, also called a light chain constant region.The heavy chain of an immunoglobulin may be assigned to one of fiveclasses, called a (IgA), Ii (IgD), E (IgE), y (IgG), or μ (IgM), some ofwhich may be further divided into subclasses, e.g., γ1 (IgG1), γ2(IgG2), γ3 (IgG3), γ4 (gG4), α1 (IgA1) and α2 (IgA2). The light chain ofan immunoglobulin may be assigned to one of two types, kappa (κ) orlambda (L), based on the amino acid sequence of its constant domain. Animmunoglobulin essentially consists of two Fab molecules and an Fcchain, linked via the immunoglobulin hinge region.

“Immunoconjugate” refers to a polypeptide molecule that includes atleast one IL-2Rβγc ligand and at least one antigen binding moiety. Animmunoconjugate can comprise at least one IL-2Rβγc ligand, and at leasttwo antigen binding moieties. An immunoconjugate can comprise at leastone IL-2Rβγc ligand and two antigen binding moieties joined by one ormore linker sequences. An antigen binding moiety can be joined to theIL-2Rβγc ligand by a variety of interactions and in a variety ofconfigurations.

“Amino acid sequence similarity” refers to an amino acid sequence inwhich one or more amino acids of the amino has been replaced with achemically similar amino acid. Examples of chemically similar aminoacids include (a) amino acids having a small hydrophobic side chain suchas alanine (A), glycine (G), proline (P), serine (S), or threonine (T);(b) amino acids having a hydroxyl-containing side chain such as serine(S), threonine (T), or tyrosine (Y); (c) amino acids having an acidicside chain such as aspartate (D) or glutamate (E); (d) amino acidshaving a polar-neutral side chain such as histidine (H), asparagine (N),glutamine (Q), serine (S), threonine (T), or tyrosine (Y); (e) aminoacids having a basic side chain such as arginine (R), lysine (K), orhistidine (H); (f) amino acids having a large hydrophobic side chainsuch as isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W); and (g) amino acidshaving an aromatic side chain comprising phenylalanine (F), histidine(H), tryptophan (W), or tyrosine (Y). A chemically similar amino acidcan comprise a naturally occurring amino acid or a non-natural aminoacid.

“Percent (%) sequence similarity” refers to amino acid sequences inwhich one or more amino acids of a reference amino acid sequence isreplaced with an amino acid such as a chemically similar amino acid. Forexample, given a reference amino acid sequence-RDQYYPCWMAQLGELCDLDEVF-(SEQ ID NO: 1037), the amino acid sequence-RDQYYPCYMAQLGELCDLEEVF-(SEQ ID NO: 1038) represents a similar aminoacid sequence, in which an amino acid W having aromatic side chain isreplaced with chemically similar amino acid Y having an aromatic sidechain; and an amino acid D having an acidic side chain is replaced withchemically similar amino acid E having an acidic side chain. Referringto this example, the similar amino acid sequence, which consists of 22amino acids, has a 90.9% (2/22) sequence similarity to the referenceamino acid sequence.

“Percent (%) sequence similarity” is determined by comparing the numberof amino acids that are the same in a subject peptide ligand and areference peptide ligand. A peptide ligand provided by the presentdisclosure can comprise, for example, greater than 70%, greater than80%, or greater than 90% sequence similarity to a reference peptideligand. For example, based on a reference peptide ligand having SEQ IDNO: 1030, peptide ligands having SEQ-ID NOS: 1031-1036, have either 1,2, 3, 4, or 5 amino acid in which an amino acid of the reference peptidehas been substituted or replaced with the amino acid, alanine. Peptideligands having SEQ ID NOS: 1031-1036 are characterized by a 95%, 90%,85%, 80%, 75%, or 70% sequence similarity, respectively, to the aminoacid sequence of the reference peptide.

SEQ ID NO: 1030 Y P C W L A R V G E L C D L D S G D V H SEQ ID NO: 1031A P C W L A R V G E L C D L D S G D V H SEQ ID NO: 1032 A P C A L A R VG E L C D L D S G D V H SEQ ID NO: 1033 A P C A L A A V G E L C D L D SG D V H SEQ ID NO: 1034 A P C A L A A V G A L C D L D S G D V H SEQ IDNO: 1035 A P C A L A A V G A L C D L A S G D V H SEQ ID NO: 1036 A P C AL A A V G A L C D L A A G D V H

A peptide ligand provided by the present disclosure can have an aminoacid sequence in which from 1 to 5 amino acids of a reference amino acidsequence is substituted with another amino acid.

For example, a peptide ligand derived from a reference peptide ligandcan have from 1 to 5 amino acid substitutions, from 1 to 4, from 1 to 3,or from 1 to 2 amino acid substitutions. For example, a peptide ligandderived from a reference peptide ligand can have 1 amino acidsubstitution, 2 amino acid substitutions, 3 amino acid substitutions, 4amino acid substitutions, or 5 amino acid substitutions.

An amino acid substitution can be independent of the other amino acidsubstitutions.

Each amino acid substitution can independently be a conservative aminoacid substitution or a non-conservative amino acid substitution.

A conservative amino acid substitution refers to one of the followingamino acid substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

For example, a reference peptide ligand can have the amino acid sequenceof SEQ ID NO: 1020.

SEQ ID NO: 1020 Y W C W M A Q V G E L C D L SEQ ID NO: 1021Y H C W M A Q V G E L C D L SEQ ID NO: 1022 Y H C W M G Q V G E L C D LSEQ ID NO: 1023 Y H C W M G Q M G E L C D L SEQ ID NO: 1024Y H C W M G Q M G E L C E L SEQ ID NO: 1025 Y H C W M G Q M G E L C E M

Peptide ligands having SEQ ID NOS: 1021-1025 represent peptide ligandsin which the reference peptide ligand having SEQ ID NO: 1020 has beensubstituted with from 1 to 5 conservative amino acid substitutions,respectively.

A peptide ligand provided by the present disclosure can comprise atruncated peptide ligand. A truncated peptide ligand refers to a peptideligand in which from 1 to 5 amino acids have independently been removedfrom the N-terminus, the C-terminus, or from both the N-terminus and theC-terminus of the corresponding reference peptide ligand. A truncatedpeptide ligand derived from the corresponding reference peptide ligandcan independently have from 1 to 5 amino acids, such as from 1 to 4amino acids, from 1 to 3 amino acids, or from 1 to 2 amino acidsindependently removed from the N-terminus, the C-terminus, or from boththe N-terminus and the C-terminus of the reference peptide ligand. Atruncated peptide ligand derived from the corresponding referencepeptide ligand can independently have 1 amino acid, 2 amino acids, 3amino acids, 4 amino acids, or 5 amino acids removed from theN-terminus, the C-terminus, or from both the N-terminus and theC-terminus of the reference peptide ligand.

For example, a reference peptide ligand can have the amino acid sequenceof SEQ ID. NO: 1000. Examples of truncated peptide ligands derived fromthe reference peptide ligand of SEQ ID. NO: 1000 include truncatedpeptide ligands of amino acid sequence of SEQ ID NOS: 1001-1008.

SEQ ID NO: 1000 M G F Y P C W T A Q L G E L C D L S V D SEQ ID NO: 1001  G F Y P C W T A Q L G E L C D L S V D SEQ ID NO: 1002    F Y P C W T A Q L G E L C D L S V D SEQ ID NO: 1003      Y P C W T A Q L G E L C D L S V D SEQ ID NO: 1004M G F Y P C W T A Q L G E L C D L S V SEQ ID NO: 1005M G F Y P C W T A Q L G E L C D L S  SEQ ID NO: 1006M G F Y P C W T A Q L G E L C D L  SEQ ID NO: 1007  G F Y P C W T A Q L G E L C D L S V SEQ ID NO: 1008    F Y P C W T A Q L G E L C D L

The truncated peptide ligands of SEQ ID NOS: 1001-1003 have amino acidsremoved from the N-terminus of the reference peptide ligand; truncatedpeptide ligands of SEQ ID NOS: 1004-1006 have amino acids removed fromthe C-terminus of the reference peptide ligand; and truncated peptideligands of SEQ ID NOS: 1007-1008 have amino acids removed from both theN-terminus and from the C-terminus of the reference peptide ligand.

As another example, a reference peptide ligand can comprise an aminoacid sequence of Formula (A):

—X⁵⁰⁰—X⁵⁰¹—C—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—C—X⁵¹⁰—X⁵¹¹  (A)

where each —X— independently represents an amino acid. Amino acidsequences of Formula (A1)-(A2) represent truncated peptide ligandsderived from the reference peptide ligand comprising the amino acidsequence of Formula (A):

—X⁵⁰¹—C—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—C—X⁵¹⁰—X⁵¹¹—  A1)

—C—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—C—X⁵¹⁰—X⁵¹¹  (A2)

—C—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—C—  (A3)

—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—C—X⁵¹⁰—  (A4)

—X⁵⁰²—X⁵⁰³—X⁵⁰⁴—X⁵⁰⁵—X⁵⁰⁶—X⁵⁰⁷—X⁵⁰⁸—X⁵⁰⁹—  (A5)

A peptide ligand provided by the present disclosure can comprise anamino acid sequence in which from 1 to 3 glycines are independentlybonded to the N-terminus, to the C-terminus, or to both the N-terminusand to the C-terminus of a reference peptide ligand.

SEQ ID NO: 1010       K Y C G F A Q L G E L C V L SEQ ID NO: 1011    G K Y C G F A Q L G E L C V L SEQ ID NO: 1012  G G K Y C G F A Q L G E L C V L SEQ ID NO: 1013G G G K Y C G F A Q L G E L C V L SEQ ID NO: 1014      K Y C G F A Q L G E L C V L G SEQ ID NO: 1015      K Y C G F A Q L G E L C V L G G SEQ ID NO: 1016      K Y C G F A Q L G E L C V L G G G SEQ ID NO: 1017  G K Y C G F A Q L G E L C V L G SEQ ID NO: 1018G G K Y C G F A Q L G E L C V L G

For example, reference peptide ligand can have SEQ ID NO: 1010. Peptideligands having SEQ ID NOS: 1011-1013 have from 1 to 3 glycines bonded tothe N-terminus of the reference peptide ligand, respectively; peptideligands having SEQ ID NOS: 1014-1016 have from 1 to 3 glycines bonded tothe C-terminus of the reference peptide ligand, respectively; andpeptide ligands having SEQ ID NOS: 1017-1018 independently have 1 or 2glycines bonded to both the N-terminus and to the C-terminus of thereference peptide ligand.

A peptide ligand can comprise a truncated peptide ligand in which from 1to 3 glycines are independently bonded to the N-terminus, to theC-terminus, or to both the N-terminus and to the C-terminus of areference truncated peptide ligand.

“IL-2Rα binding compound” refers to an IL-2Rα ligand provided by thepresent disclosure, a tandem IL-2Rα ligand provided by the presentdisclosure, an IL-2Rα ligand construct provided by the presentdisclosure, and a construct comprising at least one IL-2Rα ligand and atleast one IL-2Rβ ligand and/or at least one IL-2Rγc ligand.

The expression “at least one” refers to “one or more.” For example, theexpression at least can refer to from 1 to 10, from 1 to 8, from 1 to 6,from 1 to 5, from 1 to 4, from 1 to 3, or from 1 to 2. For example, theexpression at least one can refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

IL-2Rα ligands provided by the present disclosure comprise peptidedomains amenable to strategies to simultaneously mask peripheralbioactivity, target delivery to a tumor, selectively activate cytotoxicanti-tumor cells, and direct IL-2 receptor activation at tumor sites.IL-2R agonists provided by the present disclosure can also be used totreat autoimmune diseases.

IL-2R agonists can be designed to selectively activate a specific formof the IL-2 receptor. The small peptide IL-2R ligands, having an aminoacid sequence that is unrelated to that of the natural cytokine, canselectively bind to and activate the IL-2Rα subunit to producetherapeutic IL-2 activity. Because the IL-2R peptidyl ligands are small,i.e. from 5 to 20 amino acids, with very low immunogenic potential, thesmall peptidyl IL-2R ligands can be incorporated into compounds toenhance therapeutic efficacy. For example, this allows the affinity ofthe IL-2R peptidyl ligands for each of the three IL-2R subunits to betuned to direct the responsiveness of a particular immune cellpopulation and affords flexibility to chemically target to tumor sitesand mediate the immune response.

IL-2Rβ and IL-2Rγc ligands and compounds comprising IL-2Rβ and IL-2Rγcligands are disclosed in U.S. Provisional Application No. 62/715,097filed on Aug. 6, 2018, which is incorporated by reference in itsentirety.

The present disclosure is directed to IL-2Rα ligands and compoundscomprising IL-2Rα ligands. The compounds comprising IL-2Rα ligands cancomprise an IL-2Rβ ligand and/or an IL-2Rγc ligand.

Peptides having a binding affinity to IL-2Rα can be identified by randompeptide diversity generating systems in conjunction with an affinityenrichment process, for example, using peptides on plasmids or peptideson phage systems.

Peptidyl ligands for the IL-2Rα subunit can be identified from highlycomplex peptide diversity libraries such as phage display libraries,optimized by peptide synthesis, and can be assembled into monomers,homo-oligomers, heteromers or incorporated into other compounds.

Random peptides can be presented either on the surface of a phageparticle, as part of a fusion protein comprising either the pIII or thepVIII coat protein of a phage fd derivative (peptides on phage) or as afusion protein with the LacI peptide fusion protein bound to a plasmid(peptides on plasmids). The phage or plasmids, including the DNAencoding the peptides, can be identified and isolated by an affinityenrichment process using an immobilized IL-2Rα subunit. The affinityenrichment process, sometimes referred to as “panning,” involvesmultiple rounds of incubating the phage or plasmids with the immobilizedreceptor, collecting the phage or plasmids that bind to the receptor(along with the accompanying DNA), and producing more of the phage orplasmids (along with the accompanying LacI-peptide fusion protein)collected. The extracellular domain (ECD) of the IL-2Rα subunit can beused during panning.

After several rounds of affinity enrichment, the phage or plasmids andaccompanying peptides were examined by ELISA to determine if thepeptides bind specifically to the IL-2Rα subunit. The assay can beperformed using methods similar to those described for the affinityenrichment process, except that after removing unbound phage, the wellscan be treated with an antibody such as a rabbit anti-phage antibody andthen with alkaline phosphatase (AP)-conjugated goat anti-rabbitantibody. The amount of alkaline phosphatase in each well can bedetermined by standard methods.

By comparing test wells with control wells without the IL-2 receptor,one can determine whether the fusion proteins bind to the receptorspecifically. The phage pools found to bind to the IL-2Rα subunit can bescreened in a colony lift probing format using monovalent or divalentreceptor.

IL-2Rα ligands can also be identified by panning subunits fused to Fc.

Peptides found to bind specifically to the IL-2Rα subunit can then besynthesized as the free peptide (e.g., no phage) and tested in ablocking assay. The blocking assay can be carried out in a similarmanner to the ELISA, except that IL-2Rα binding peptides or a referencepeptide at different concentrations can be added to the wells before thetracer peptide or fusion protein (the control wells can be of two types:(1) no receptor; and (2) IL-2Rα subunit binding peptide or referencepeptide). Tracer peptides or fusion protein in the instance compriseIL-2Rα ligands wherein binding to immobilized IL-2Rα can be detected bya variety of means.

The IL-2 receptor, as well as its extracellular domain, can be producedin recombinant host cells.

Screening methods used to identify peptides that bind to IL-2Rα caninvolve first identifying lead peptides which bind to the extracellulardomain of the receptor and then synthesizing other peptides whichresemble the lead peptides. Specifically, using a pIII or pVIII-basedpeptides on a phage system, a random library can be screened to discovera phage that presents a peptide that binds to the IL-2Rα subunit. Thephage DNAs are sequenced to determine the sequences of the peptidesdisplayed on the surface of the phages.

For example, clones capable of specific binding to IL-2Rα can beidentified from a random linear or disulfide-bridged cyclic 10-mer pVIIIlibrary and a random linear or disulfide-bridged cyclic 12-mer pVIIIlibrary. The sequences of these peptides can serve as the basis for theconstruction of other peptide libraries designed to contain a highfrequency of derivatives of the initially identified peptides. Theselibraries can be synthesized so as to favor the production of peptidesthat differ from the binding peptide in only a few residues. Thisapproach involves the synthesis of an oligonucleotide with the bindingpeptide coding sequence, except that rather than using pure preparationsof each of the four nucleoside triphosphates in the synthesis, mixturesof the four nucleoside triphosphates (i.e., 55% of the “correct”nucleotide, and 15% each of the other three nucleotides is one preferredmixture for this purpose and 70% of the “correct” nucleotide and 10% ofeach of the other three nucleotides is another preferred mixture forthis purpose) can be used so as to generate derivatives of the bindingpeptide coding sequence.

A variety of strategies can be used to derivatize the lead peptides bymaking “mutagenesis on a theme” libraries, including a pVIII phagemidmutagenesis library based on the consensus sequence and mutagenized at70:10:10:10 frequency with 5 NNK codons on each terminus (probing withradiolabeled monovalent receptor and with or without peptide elution).

The “peptides on plasmids” method can also be used for peptide screeningand mutagenesis studies. According to this approach, random peptides canbe fused at the C-terminus of LacI through expression from a plasmidvector carrying the fusion gene. Linkage of the LacI-peptide fusion toits encoding DNA occurs via the lacO sequences on the plasmid, forming astable peptide-LacI-plasmid complex that can be screened by affinitypurification (panning) on an immobilized receptor. The plasmids thusisolated can then be reintroduced into E. coli by electroporation toamplify the selected population for additional rounds of screening, orfor the examination of individual clones.

In addition, random peptide screening and mutagenesis studies can beperformed using a modified C-terminal Lac-I display system in whichdisplay valency was reduced (“headpiece dimer” display system). Thelibraries can be screened, and the resulting DNA inserts were cloned asa pool into a maltose binding protein (MBP) vector allowing theirexpression as a C-terminal fusion protein. Crude cell lysates fromrandomly picked individual MBP fusion clones were then assayed forIL-2Rα binding in an ELISA format, as discussed above.

A variety of methods can be used to evaluate IC₅₀ values. For example,an equilibrium binding ELISA assay, an IL-2 or IL-2Rα peptide tracer,was used to determine whether the peptides inhibit the binding of thetracer to the extracellular domain of IL-2α. The IC₅₀ value can bedetermined using the free peptide, which optionally can be C-terminallyamidated, or can be prepared as an ester or other carboxy amide. Torecreate the exact sequence displayed by the phage, the N-terminal andC-terminal amino acids of the synthetic peptides are often preceded byone or two glycine residues. These glycines are not believed to benecessary for binding or activity.

Synthetic peptide library technologies such as DNA-encoded peptidelibraries can also be used.

In general, peptides and peptidomimetics having an IC₅₀ of greater than100 μM lack sufficient binding affinity to be useful in imaging,targeting, diagnostic, and therapeutic applications. For imaging,targeting or diagnostic purposes, peptides and peptidomimetics can havean IC₅₀, for example, of 1 μM or less and, for pharmaceutical purposes,peptides and peptidomimetics can have an IC₅₀, for example, less than100 μm, or less than 100 nm.

An IL-2Rα ligand provided by the present disclosure can bind to thehuman IL-2Rα subunit with an IC₅₀, for example, of less than 100 μM,less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rα ligand provided by the present disclosure can bind to thehuman IL-2Rα subunit with an IC₅₀, for example, from 1 μM to 100 μM,from 10 μM to 10 μM, from 100 μM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rα ligand provided by the present disclosure can bind to amammalian IL-2Rα subunit with an IC₅₀, for example, of less than 100 μM,less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rα ligand provided by the present disclosure can bind to amammalian IL-2Rα subunit with an IC₅₀, for example, from 1 μM to 100 μM,from 10 μM to 10 μM, from 100 μM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rα ligand provided by the present disclosure can have an aminoacid sequence of any one of SEQ ID NOS: 1-307 and 400-423.

An IL-2Rα ligand provided by the present disclosure can have greaterthan 70% sequence similarity, greater than 75% sequence similarity,greater than 80%, greater than 85% sequence similarity, greater than 90%sequence similarity, or greater than 95% sequence similarity to any oneof SEQ ID NOS: 1-307 and 400-423.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (1) (SEQ ID NO: 1):

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (1)

wherein,

-   -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain or an aromatic side chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid;    -   X⁴ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁵ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar/neutral side chain;    -   X⁶ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁷ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁸ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid comprising a        polar/neutral side chain;    -   X¹¹ can be selected from an amino acid comprising a large        hydrophobic side chain;

and

-   -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (1), X¹ can be selected from F, H, I, L, M,V, W, and Y.

In IL-2Rα ligands of Formula (1), X² can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (1), X³ can be selected from A, D, E, F, G,H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (1), X⁴ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (1), X⁵ can be selected from H, N, Q, Y, A,G, P, S, and T.

In IL-2Rα ligands of Formula (1), X⁶ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (1), X⁷ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (1), X⁹ can be selected from A, G, P, S,and T.

In IL-2Rα ligands of Formula (1), X¹⁰ can be selected from H, N, Q, S,T, and Y.

In IL-2Rα ligands of Formula (1), X¹¹ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rα ligands of Formula (1), X¹² can be selected from F, I, L, M,V, W, and Y.

In IL-2Rα ligands of Formula (1), X¹ can be selected from L, W, and F.

In IL-2Rα ligands of Formula (1), X² can be selected from D, A, L, andV.

In IL-2Rα ligands of Formula (1), X³ can be selected from L, V, H, P,and E.

In IL-2Rα ligands of Formula (1), X⁴ can be selected from T, D, and W.

In IL-2Rα ligands of Formula (1), X⁵ can be selected from Y, W, P, andQ.

In IL-2Rα ligands of Formula (1), X⁶ can be selected from D, S, V, andA.

In IL-2Rα ligands of Formula (1), X⁷ can be selected from E and Y.

In IL-2Rα ligands of Formula (1), X⁸ can be selected from L and F.

In IL-2Rα ligands of Formula (1), X⁹ can be selected from L, R, and S.

In IL-2Rα ligands of Formula (1), X¹⁰ can be selected from A, R, and Q.

In IL-2Rα ligands of Formula (1), X¹¹ can be selected from C, R, V, andM.

In IL-2Rα ligands of Formula (1), X¹² can be selected from T, L, and M.

In IL-2Rα ligands of Formula (1), X¹ can be F.

In IL-2Rα ligands of Formula (1), X² can be selected from L and V.

In IL-2Rα ligands of Formula (1), X³ can be selected from A, D, E, F, G,H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (1), X⁴ can be W.

In IL-2Rα ligands of Formula (1), X⁵ can be P.

In IL-2Rα ligands of Formula (1), X⁶ can be V.

In IL-2Rα ligands of Formula (1), X⁷ can be Y.

In IL-2Rα ligands of Formula (1), X⁸ can be F.

In IL-2Rα ligands of Formula (1), X⁹ can be S.

In IL-2Rα ligands of Formula (1), X¹⁰ can be Q.

In IL-2Rα ligands of Formula (1), X¹¹ can be selected from N and V.

In IL-2Rα ligands of Formula (1), X¹² can be selected from L and M.

In IL-2Rα ligands of Formula (1), X¹ can be F, X⁴ can be W, X⁵ can be P,X⁶, can be V, X⁷ can be Y, X⁸ can be F, X⁹ can be S, and X¹⁰ can be Q.

In IL-2Rα ligands of Formula (1),

X¹ can be F;

X² can be selected from F, H, I, L, M, V, W, and Y;

X³ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁴ can be W;

X⁵ can be selected from H, N, Q, Y, A, G, P, S, and T;

X⁶ can be V;

X⁷ can be Y;

X⁸ can be F;

X⁹ can be S;

X¹⁰ can be Q;

X¹¹ can be selected from F, I, L, M, V, W, and Y; and

X¹² can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 2 to SEQ ID NO: 6:

SEQ ID NO: 2 L D L T Y D E L L A C T SEQ ID NO: 3W A Y D W S C F R R R L SEQ ID NO: 4 F L H W P V Y F C Q V MSEQ ID NO: 5 F L P W P V Y F S Q V L SEQ ID NO: 6F V E W Q A Y F S Q M M

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO:6.

An IL-2Rα ligands provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 1 to SEQ ID NO:6, or a truncated amino acid sequence of any one of SEQ ID NO: 1 to SEQID NO: 6, wherein the amino acid sequence can independently comprisefrom 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rα ligands provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 1 to SEQ ID NO:6, or a truncated amino acid sequence of any one of SEQ ID NO: 1 to SEQID NO: 6, wherein the amino acid sequence comprises one or more aminoacid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (2) (SEQ ID NO: 7):

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (2)

wherein,

-   -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁴ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁵ can be selected from an amino acid comprising an acidic side        chain;    -   X⁶ can be selected from an amino acid comprising an acidic side        chain;    -   X⁷ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁸ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁹ can be selected from an amino acid;    -   X¹⁰ can be selected from an amino acid comprising a        polar/neutral side chain;    -   X¹¹ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (2), X¹ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (2), X² can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (2), X³ can be selected from A, G, P, S,and T.

In IL-2Rα ligands of Formula (2), X⁴ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (2), X⁶ can be selected from D and E.

In IL-2Rα ligands of Formula (2), X⁷ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (2), X⁸ can be selected from F, I, L, M, V,W, and Y.

In IL-2Rα ligands of Formula (2), X⁹ can be selected from A, D, E, F, G,H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (2), X¹⁰ can be selected from H, N, Q, S,T, and Y.

In IL-2Rα ligands of Formula (2), X¹¹ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rα ligands of Formula (2), X¹² can be selected from F, I, L, M,V, W, and Y.

In IL-2Rα ligands of Formula (2), X¹ can be F.

In IL-2Rα ligands of Formula (2), X² can be selected from I, L, and V.

In IL-2Rα ligands of Formula (2), X³ can be P.

In IL-2Rα ligands of Formula (2), X⁴ can be W.

In IL-2Rα ligands of Formula (2), X⁵ can be selected from P, D, and E.

In IL-2Rα ligands of Formula (2), X⁶ can be selected from V and E.

In IL-2Rα ligands of Formula (2), X⁷ can be Y.

In IL-2Rα ligands of Formula (2), X⁸ can be F.

In IL-2Rα ligands of Formula (2), X⁹ can be S, A, K, and L.

In IL-2Rα ligands of Formula (2), X¹⁰ can be Q.

In IL-2Rα ligands of Formula (2), X¹¹ can be selected from V, I, and L.

In IL-2Rα ligands of Formula (2), X¹² can be selected from L and M.

In IL-2Rα ligands of Formula (2), X¹ can be F.

In IL-2Rα ligands of Formula (2), X² can be selected from L and V.

In IL-2Rα ligands of Formula (2), X³ can be P.

In IL-2Rα ligands of Formula (2), X⁴ can be W.

In IL-2Rα ligands of Formula (2), X⁵ can be D.

In IL-2Rα ligands of Formula (2), X⁶ can be E.

In IL-2Rα ligands of Formula (2), X⁷ can be Y.

In IL-2Rα ligands of Formula (2), X⁸ can be F.

In IL-2Rα ligands of Formula (2), X⁹ can be selected from A, D, E, F, G,H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (2), X⁹ can be S.

In IL-2Rα ligands of Formula (2), X¹⁰ can be Q.

In IL-2Rα ligands of Formula (2), X¹¹ can be selected from I, L, and V.

In IL-2Rα ligands of Formula (2), X¹² can be L.

In IL-2Rα ligands of Formula (2), X¹ can be F, X³ can be P, X⁴ can be W,X⁵ can be D, X⁶, can be E, X⁷ can be Y, X⁸ can be F, X¹⁰ can be Q, andX¹² can be L.

In IL-2Rα ligands of Formula (2),

X¹ can be F;

X² can be selected from F, I, L, M, V, W, and Y;

X³ can be P;

X⁴ can be W;

X⁵ can be selected from D and P;

X⁶ can be E;

X⁷ can be Y;

X⁸ can be F;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be Q;

X¹¹ can be selected from F, I, L, M, V, W, and Y; and

X¹² can be L.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 8 to SEQ ID NO: 15:

SEQ ID NO: 8 F I F A Q A Q L L SEQ ID NO: 9 F I P W D E Y F K Q V LSEQ ID NO: 10 F V P W D V Y F S Q I L SEQ ID NO: 11F I P W D E Y F K Q V L  SEQ ID NO: 12 F V P W P E Y F L Q I MSEQ ID NO: 13 F I P W E E Y F S Q L L SEQ ID NO: 14F I P W P E Y F S Q L L SEQ ID NO: 15 F V P W D E Y F L Q I L

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 7 to SEQ ID NO:15.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 7 to SEQ ID NO:15, or a truncated amino acid sequence of any one of SEQ ID NO: 7 to SEQID NO: 15, wherein the amino acid sequence can independently comprisefrom 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 7 to SEQ ID NO:15, or a truncated amino acid sequence of any one of SEQ ID NO: 7 to SEQID NO: 15, wherein the amino acid sequence comprises one or more aminoacid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (3a) (SEQ ID NO: 16), the amino acid sequenceof Formula (3b) (SEQ ID NO: 17), or the amino acid sequence of Formula(3c) (SEQ ID NO: 18):

—X⁵—X⁶—X⁷—X⁸—  (3a)

—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—  (3b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (3c)

wherein,

-   -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from amino acid comprising a small        hydrophobic side chain;    -   X⁹ can be C;    -   X¹⁰ can be selected from an amino acid comprising a basic side        chain or a polar/neutral side chain;    -   X¹¹ can be selected from an amino acid comprising a small        hydrophobic side chain; and    -   X¹² can be selected from an amino acid.

In IL-2Rα ligands of Formula (3a)-(3c), X¹ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X² can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X³ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁴ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X⁵ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (3a)-(3c), X⁶ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁷ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁸ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (3a)-(3c), X⁹ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X¹⁰ can be selected from H, K,N, Q, R, S, T, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X¹¹ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (3a)-(3c), X¹² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X¹ can be selected from Y and W.

In IL-2Rα ligands of Formula (3a)-(3c), X² can be V.

In IL-2Rα ligands of Formula (3a)-(3c), X³ can be selected from M and I.

In IL-2Rα ligands of Formula (3a)-(3c), X⁴ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X⁵ can be S.

In IL-2Rα ligands of Formula (3a)-(3c), X⁶ can be A.

In IL-2Rα ligands of Formula (3a)-(3c), X⁷ can be F, L, V, and M.

In IL-2Rα ligands of Formula (3a)-(3c), X⁸ can be G.

In IL-2Rα ligands of Formula (3a)-(3c), X⁹ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X¹⁰ can be selected from K andR.

In IL-2Rα ligands of Formula (3a)-(3c), X¹¹ can be selected from S, P,and A.

In IL-2Rα ligands of Formula (3a)-(3c), X¹² can be selected from I, L,M, F, and W.

In IL-2Rα ligands of Formula (3a)-(3c), X¹ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X² can be V.

In IL-2Rα ligands of Formula (3a)-(3c), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁴ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X⁵ can be G.

In IL-2Rα ligands of Formula (3a)-(3c), X⁶ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁷ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X⁸ can be G.

In IL-2Rα ligands of Formula (3a)-(3c), X⁹ can be C.

In IL-2Rα ligands of Formula (3a)-(3c), X¹⁰ can be R.

In IL-2Rα ligands of Formula (3a)-(3c), X¹¹ can be S.

In IL-2Rα ligands of Formula (3a)-(3c), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (3a)-(3c), X¹² can be V.

In IL-2Rα ligands of Formula (3a)-(3c), X² can be V, X⁴ can be C, X⁵ canbe G, X⁸ can be G, X⁹ can be C, X¹⁰ can be R, and X¹¹ can be S.

In IL-2Rα ligands of Formula (3a)-(3c),

X¹ can be selected from F, I, L, M, V, W, and Y;

X² can be V;

X³ can be selected from F, I, L, M, V, W, and Y;

X⁴ can be C;

X⁵ can be G;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be G;

X⁹ can be C;

X¹⁰ can be R;

X¹¹ can be S; and

X¹² can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 19 to SEQ ID NO: 24:

SEQ ID NO: 19 F V L C G L Q G C R G S SEQ ID NO: 20 K V I C G W D G C RSEQ ID NO: 21 L V F C G K N G C H S G SEQ ID NO: 22V V L C T P K G C R S A SEQ ID NO: 23 Y V M C S A F G C K S ISEQ ID NO: 24 F V H C T L L G C W S G

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 16 to SEQ ID NO:24.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 16 to SEQ ID NO:24, or a truncated amino acid sequence of any one of SEQ ID NO: 16 toSEQ ID NO: 24, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 16 to SEQ ID NO:24, or a truncated amino acid sequence of any one of SEQ ID NO: 16 toSEQ ID NO: 24, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (4a) (SEQ ID NO: 25), the amino acid sequenceof Formula (4b) (SEQ ID NO: 26), the amino acid sequence of Formula (4c)(SEQ ID NO: 27), or the amino acid sequence of Formula (4d) (SEQ ID NO:28):

—X⁵—X⁶—X⁷—X⁸—X⁹—  (4a)

—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—  (4b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—X¹¹—  (4c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (4d)

wherein,

-   -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁷ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁸ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁹ can be C;    -   X¹⁰ can be selected from an amino acid comprising a basic side        chain;    -   X¹¹ can be selected from an amino acid comprising a small        hydrophobic side chain; and    -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (4a)-(4d), X¹ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X² can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X⁴ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X⁵ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (4a)-(4d), X⁶ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (4a)-(4d), X⁷ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X⁸ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (4a)-(4d), X⁹ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X¹⁰ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (4a)-(4d), X¹¹ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (4a)-(4d), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X¹ can be selected from Y and W.

In IL-2Rα ligands of Formula (4a)-(4d), X² can be V.

In IL-2Rα ligands of Formula (4a)-(4d), X³ can be selected from M and I.

In IL-2Rα ligands of Formula (4a)-(4d), X⁴ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X⁵ can be S.

In IL-2Rα ligands of Formula (4a)-(4d), X⁶ can be A.

In IL-2Rα ligands of Formula (4a)-(4d), X⁷ can be selected from F, L, V,and M.

In IL-2Rα ligands of Formula (4a)-(4d), X⁸ can be G.

In IL-2Rα ligands of Formula (4a)-(4d), X⁹ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X¹⁰ can be selected from R andK.

In IL-2Rα ligands of Formula (4a)-(4d), X¹¹ can be selected from S, P,and A.

In IL-2Rα ligands of Formula (4a)-(4d), X¹² can be selected from I, M,F, and W.

In IL-2Rα ligands of Formula (4a)-(4d), X¹ can be W.

In IL-2Rα ligands of Formula (4a)-(4d), X² can be V.

In IL-2Rα ligands of Formula (4a)-(4d), X³ can be I.

In IL-2Rα ligands of Formula (4a)-(4d), X⁴ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X⁵ can be S.

In IL-2Rα ligands of Formula (4a)-(4d), X⁶ can be A.

In IL-2Rα ligands of Formula (4a)-(4d), X⁷ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X⁸ can be G.

In IL-2Rα ligands of Formula (4a)-(4d), X⁹ can be C.

In IL-2Rα ligands of Formula (4a)-(4d), X¹⁰ can be R.

In IL-2Rα ligands of Formula (4a)-(4d), X¹¹ can be S.

In IL-2Rα ligands of Formula (4a)-(4d), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (4a)-(4d), X¹ can be W, X² can be V, X³ canbe I, X⁴ can be C, X⁵ can be S, X⁶ can be A, X⁸ can be G, X⁹ can be C,X¹⁰ can be R, and X¹¹ can be S.

In IL-2Rα ligands of Formula (4a)-(4d),

X¹ can be W;

X² can be V;

X³ can be I;

X⁴ can be C;

X⁵ can be S;

X⁶ can be A;

X⁷ can be selected from F, I, L, M, V, W, and Y.

X⁸ can be G;

X⁹ can be C;

X¹⁰ can be selected from R and K;

X¹¹ can be S; and

X¹² can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 29 to SEQ ID NO: 36:

SEQ ID NO: 29 W V I C S A L G C R S L SEQ ID NO: 30W V I C S A L G C R S M SEQ ID NO: 31 W V I C S A V G C R P F SEQ ID NO: 32 W V I C S A M G C R S I SEQ ID NO: 33W V I C S A L G C R S I SEQ ID NO: 34 W V I C S A F G C R S MSEQ ID NO: 35 W V I C S A L G C R P F SEQ ID NO: 36W V I C S A L G C K A W

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 25 to SEQ ID NO:36.

An IL-2Rα ligand†s provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 25 to SEQ ID NO:36, or a truncated amino acid sequence of any one of SEQ ID NO: 25 toSEQ ID NO: 36, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand†s provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 25 to SEQ ID NO:36, or a truncated amino acid sequence of any one of SEQ ID NO: 25 toSEQ ID NO: 36, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (5a) (SEQ ID NO: 37), the amino acid sequenceof Formula (5b) (SEQ ID NO: 38), the amino acid sequence of Formula (5c)(SEQ ID NO: 39), or the amino acid sequence of Formula (5d) (SEQ ID NO:40):

—X⁵—X⁶—X⁷—X⁸—X⁹—  (5a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—C—X¹¹—  (5b)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—C—X¹¹—X¹²—  (5c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (5d)

wherein,

-   -   X¹ can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a small        hydrophobic side chain or an acidic side chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be C;    -   X¹¹ can be selected from an amino acid comprising a basic side        chain; and    -   X¹² can be selected from an amino acid.

In IL-2Rα ligands of Formula (5a)-(5d), X¹ can be selected from F, H, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X² can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁴ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be selected from A, G, H,K, P, R, S, and T.

In IL-2Rα ligands of Formula (5a)-(5d), X⁶ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁷ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁸ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁹ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (5a)-(5d), X¹⁰ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X¹¹ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (5a)-(5d), X¹² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X¹ can be selected from F, H, W,and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X² can be V.

In IL-2Rα ligands of Formula (5a)-(5d), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁴ can be selected from F, K, L,V, W, and H.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be V.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be selected from L, F, M,H, T, A, and I.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X⁶ can be selected from G, T, S,R, and K.

In IL-2Rα ligands of Formula (5a)-(5d), X⁶ can be selected from L, W, K,P, A, N, W, and V,

In IL-2Rα ligands of Formula (5a)-(5d), X⁷ can be selected from Q, D, N,K, F, L, R, G, and D.

In IL-2Rα ligands of Formula (5a)-(5d), X⁸ can be selected from G, N, Y,H, and G.

In IL-2Rα ligands of Formula (5a)-(5d), X⁹ can be G.

In IL-2Rα ligands of Formula (5a)-(5d), X¹⁰ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X¹¹ can be selected from G, S,R, T, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X¹² can be selected from S, G,A, I, G, P, R, and S.

In IL-2Rα ligands of Formula (5a)-(5d), X¹ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X² can be V.

In IL-2Rα ligands of Formula (5a)-(5d), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁴ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (5a)-(5d), X⁵ can be S.

In IL-2Rα ligands of Formula (5a)-(5d), X⁶ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁶ can be W.

In IL-2Rα ligands of Formula (5a)-(5d), X⁷ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁸ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X⁹ can be G.

In IL-2Rα ligands of Formula (5a)-(5d), X¹⁰ can be C.

In IL-2Rα ligands of Formula (5a)-(5d), X¹¹ can be R.

In IL-2Rα ligands of Formula (5a)-(5d), X¹² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (5a)-(5d), X² can be V, X⁴ can be C, X⁵ canbe S, X⁹ can be G, X¹⁰ can be C, and X¹¹ can be R.

In IL-2Rα ligands of Formula (5a)-(5d),

X¹ can be selected from F, H, I, L, M, V, W, and Y;

X² can be V;

X³ can be selected from F, I, L, M, V, W, and Y;

X⁴ can be C;

X⁵ can be S;

X⁶ can be selected from F, I, L, M, V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be G;

X¹⁰ can be C;

X¹¹ can be R; and

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 41 to SEQ ID NO: 45:

SEQ ID NO: 41 Y V L C S N R N G C R P SEQ ID NO: 42Y V T C R W G Y G C T R SEQ ID NO: 43 W V A C S W D H G C R SSEQ ID NO: 44 H V I C S V N G G C R G SEQ ID NO: 45W V X C K P L H G C Y G

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 37 to SEQ ID NO:45.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 37 to SEQ ID NO:45, or a truncated amino acid sequence of any one of SEQ ID NO: 37 toSEQ ID NO: 45, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 37 to SEQ ID NO:45, or a truncated amino acid sequence of any one of SEQ ID NO: 37 toSEQ ID NO: 45, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (6a) (SEQ ID NO: 46), the amino acid sequenceof Formula (6b) (SEQ ID NO: 47), the amino acid sequence of Formula (6c)(SEQ ID NO: 48), or the amino acid sequence of Formula (6d) (SEQ ID NO:49):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (6a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰⁰—X¹¹—C—X¹³—  (6b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—X¹⁴—  (6c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (6d)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid;    -   X³ can be selected from an amino acid comprising a large        hydrophobic side chain or an aromatic side chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a basic side        chain;    -   X⁷ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X⁸ can be selected from an amino acid comprising an acidic side        chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹² can be C;    -   X¹³ can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X¹⁴ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain; and    -   X¹⁵ can be selected from an amino acid.

In IL-2Rα ligands of Formula (6a)-(6d),

-   -   X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,        R, S, T, V, W, and Y;    -   X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,        R, S, T, V, W, and Y;    -   X³ can be selected from F, H, I, L, M, V, W, and Y;    -   X⁴ can be C;    -   X⁵ can be selected from F, I, L, M, V, W, and Y;    -   X⁶ can be selected from H, K, and R;    -   X⁷ can be selected from A, G, H, N, P, Q, S, T, and Y;    -   X⁸ can be selected from D and E;    -   X⁹ can be selected from A, G, P, S, and T;    -   X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,        R, S, T, V, W, and Y;    -   X¹¹ can be selected from A, G, P, S, and T;    -   X¹² can be C;    -   X¹³ can be selected from F, H, I, L, M, V, W, and Y;    -   X¹⁴ can be selected from A, G, H, N, P, Q, S, T, and Y; and    -   X¹ can be selected from any A, D, E, F, G, H, I, K, L, M, N, P,        Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X¹ can be selected from E, K, R,T, and L.

In IL-2Rα ligands of Formula (6a)-(6d), X² can be selected from Q, Y, V,K, and R.

In IL-2Rα ligands of Formula (6a)-(6d), X³ can be selected from F, W, V,and L.

In IL-2Rα ligands of Formula (6a)-(6d), X⁴ can be C.

In IL-2Rα ligands of Formula (6a)-(6d), X⁵ can be L.

In IL-2Rα ligands of Formula (6a)-(6d), X⁶ can be selected from V, R, A,and K.

In IL-2Rα ligands of Formula (6a)-(6d), X⁷ can be S.

In IL-2Rα ligands of Formula (6a)-(6d), X⁸ can be selected from D and E.

In IL-2Rα ligands of Formula (6a)-(6d), X⁹ can be P.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁰ can be selected from M, D,N, M Q, and T.

In IL-2Rα ligands of Formula (6a)-(6d), X¹¹ can be selected from A andS.

In IL-2Rα ligands of Formula (6a)-(6d), X¹² can be selected from C.

In IL-2Rα ligands of Formula (6a)-(6d), X¹³ can be selected from F andW.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁴ can be selected from S, A,and I.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁵ can be selected from L, T,M, and V.

In IL-2Rα ligands of Formula (6a)-(6d), X¹ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X² can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X³ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X⁴ can be C.

In IL-2Rα ligands of Formula (6a)-(6d), X⁵ can be L.

In IL-2Rα ligands of Formula (6a)-(6d), X⁶ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (6a)-(6d), X⁷ can be S.

In IL-2Rα ligands of Formula (6a)-(6d), X⁸ can be selected from D and E.

In IL-2Rα ligands of Formula (6a)-(6d), X⁹ can be P.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X¹¹ can be A.

In IL-2Rα ligands of Formula (6a)-(6d), X¹² can be C.

In IL-2Rα ligands of Formula (6a)-(6d), X¹³ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X¹³ can be W.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁴ can be S.

In IL-2Rα ligands of Formula (6a)-(6d), X¹⁵ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (6a)-(6d), X⁴ can be C, X⁵ can be L, X⁷ canbe S, X⁸ can be E, X⁹ can be P, X¹¹ can be A, X¹² can be C, X¹² can beW, and X¹⁴ can be S.

In IL-2Rα ligands of Formula (6a)-(6d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be selected from F, H, I, L, M, V, W, and Y;

X⁴ can be C;

X⁵ can be L;

X⁶ can be selected from H, K, and R;

X⁷ can be S;

X⁸ can be E;

X⁹ can be P;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be A;

X¹² can be C;

X¹³ can be W;

X¹⁴ can be S; and

X¹⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 50 to SEQ ID NO: 54:

SEQ ID NO: 50 E Q F C LV S D P M A C WS L SEQ ID NO: 51K Y W C L R S E P D A C F A T SEQ ID NO: 52R V Y C L A S E P N S C W S T SEQ ID NO: 53T K L C L K S E P Q A C W S M SEQ ID NO: 54I R F C L R S E P T A C W I V

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 46 to SEQ ID NO:54.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 46 to SEQ ID NO:54, or a truncated amino acid sequence of any one of SEQ ID NO: 46 toSEQ ID NO: 54, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 46 to SEQ ID NO:54, or a truncated amino acid sequence of any one of SEQ ID NO: 46 toSEQ ID NO: 54, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (7a) (SEQ ID NO: 55), the amino acid sequenceof Formula (7b) (SEQ ID NO: 56), the amino acid sequence of Formula (7c)(SEQ ID NO: 57), or the amino acid sequence of Formula (7d) (SEQ ID NO:58):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (7a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—  (7b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—X¹⁴—  (7c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (7d)

wherein,

-   -   X¹ can be selected from a basic amino acid;    -   X² can be selected from a basic amino acid;    -   X³ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a basic side        chain;    -   X⁷ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X⁸ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹¹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹² can be C;    -   X¹³ can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X¹⁴ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain; and    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (7a)-(7d),

X¹ can be selected from K, and R;

X² can be selected from H, K, and R;

X³ can be selected from F, I, L, M, V, W, and Y;

X⁴ can be C;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from H, K, and R;

X⁷ can be selected from A, G, H, N, P, Q, S, T, and Y;

X⁸ can be selected from F, I, L, M, V, W, and Y;

X⁹ can be selected from A, G, P, S, and T;

X¹⁰ can be selected from A, G, H, N, P, Q, S, T, and Y;

X¹¹ can be selected from A, G, P, S, and T;

X¹² can be C;

X¹³ can be selected from F, H, I, L, M, V, W, and Y;

X¹⁴ can be selected from A, G, H, N, P, Q, S, T, and Y; and

X¹⁵ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X¹ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X² can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X⁴ can be C.

In IL-2Rα ligands of Formula (7a)-(7d), X⁵ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X⁵ can be L.

In IL-2Rα ligands of Formula (7a)-(7d), X⁶ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (7a)-(7d), X⁷ can be selected from A, G, P,S, and T.

In IL-2Rα ligands of Formula (7a)-(7d), X⁷ can be selected from H, N, Q,S, T, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X⁷ can be S.

In IL-2Rα ligands of Formula (7a)-(7d), X⁸ can be selected from D and E.

In IL-2Rα ligands of Formula (7a)-(7d), X⁹ can be P.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X¹¹ can be A.

In IL-2Rα ligands of Formula (7a)-(7d), X¹² can be C.

In IL-2Rα ligands of Formula (7a)-(7d), X¹³ can be W.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁴ can be S.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁵ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (7a)-(7d), X¹ can be R.

In IL-2Rα ligands of Formula (7a)-(7d), X² can be R.

In IL-2Rα ligands of Formula (7a)-(7d), X³ can be F.

In IL-2Rα ligands of Formula (7a)-(7d), X⁴ can be C.

In IL-2Rα ligands of Formula (7a)-(7d), X⁵ can be L.

In IL-2Rα ligands of Formula (7a)-(7d), X⁶ can be R.

In IL-2Rα ligands of Formula (7a)-(7d), X⁷ can be S.

In IL-2Rα ligands of Formula (7a)-(7d), X⁸ can be E.

In IL-2Rα ligands of Formula (7a)-(7d), X⁹ can be P.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁰ can be T.

In IL-2Rα ligands of Formula (7a)-(7d), X¹¹ can be A.

In IL-2Rα ligands of Formula (7a)-(7d), X¹² can be C.

In IL-2Rα ligands of Formula (7a)-(7d), X¹³ can be W.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁴ can be T.

In IL-2Rα ligands of Formula (7a)-(7d), X¹⁵ can be V.

In IL-2Rα ligands of Formula (7a)-(7d), X¹ can be R, X² can be R, X³ canbe F, X⁴ can be C, X⁵ can be L, X⁶, can be R, X⁷ can be S, X⁸ can be E,X⁹ can be P, X¹⁰ can be T, X¹¹ can be A, X¹² can be C, X¹³ can be W, andX¹⁵ can be V.

In IL-2Rα ligands of Formula (7a)-(7d),

X¹ can be selected from K and R;

X² can be R;

X³ can be F;

X⁴ can be C;

X⁵ can be L;

X⁶ can be R;

X⁷ can be S;

X⁸ can be E;

X⁹ can be P;

X¹⁰ can be T;

X¹¹ can be A;

X¹² can be C;

X¹³ can be W;

X¹⁴ can be T; and

X¹⁵ can be V.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 59 to SEQ ID NO: 68:

SEQ ID NO: 59 R R F C L R S E P T A C W I V SEQ ID NO: 60K L F C L R S G D R A C W V V SEQ ID NO: 61M R F C L R S E P T A C W T V SEQ ID NO: 62R R F C L R S E P T A C W D V SEQ ID NO: 63R R F C L R S D P T A C W I V SEQ ID NO: 64K R F C L R S E P T A C W T V SEQ ID NO: 65R R F C L R S E P M A C W T V SEQ ID NO: 66R R F C L R S E P T A C W T V SEQ ID NO: 67 R R F C L R S E P AA C W F VSEQ ID NO: 68 R R F C L R S E P T A C W Y V

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 55 to SEQ ID NO:68.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 55 to SEQ ID NO:68, or a truncated amino acid sequence of any one of SEQ ID NO: 55 toSEQ ID NO: 68, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 55 to SEQ ID NO:68, or a truncated amino acid sequence of any one of SEQ ID NO: 55 toSEQ ID NO: 68, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (8a) (SEQ ID NO: 69) the amino acid sequence ofFormula (8b) (SEQ ID NO: 70), or the amino acid sequence of Formula (8c)(SEQ ID NO: 71):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (8a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—  (8b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—  (8c)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid comprising a basic side        chain;    -   X³ can be C;    -   X⁴ can be selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain;    -   X⁵ can be selected from an amino acid;    -   X⁶ can be selected from an amino acid comprising an acidic side        chain;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid;    -   X¹⁰ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be C;    -   X¹³ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁴ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (8a)-(8c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from H, K, and R;

X³ can be C;

X⁴ can be selected from F, H, I, K, L, M, R, V, W, and Y;

X⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁶ can be selected from D and E;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be selected from A, G, P, S, and T;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be C;

X¹³ can be selected from F, I, L, M, V, W, and Y; and

X¹⁴ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹ can be selected from R, I, L,M, N, S, T, V, and D.

In IL-2Rα ligands of Formula (8a)-(8c), X² can be selected from S, K, R,H, G, and F.

In IL-2Rα ligands of Formula (8a)-(8c), X³ can be C.

In IL-2Rα ligands of Formula (8a)-(8c), X⁴ can be selected from N, R, I,T, V, L, and D.

In IL-2Rα ligands of Formula (8a)-(8c), X⁵ can be selected from R, V, L,M, V, G, Y, I, F, and T.

In IL-2Rα ligands of Formula (8a)-(8c), X⁵ can be selected from Y, L, E,D, S, I, Y, D, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁶ can be selected from Y, L, E,D, S, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁷ can be selected from G, E, K,T, P, W, L, Y, G, S, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁸ can be selected from I, A, Q,R, S R, L, N, P, A, I, R, D, and W.

In IL-2Rα ligands of Formula (8a)-(8c), X⁹ can be selected from W, G, S,D, R, L, F, P, A, and T.

In IL-2Rα ligands of Formula (8a)-(8c), X¹⁰ can be selected from G, T,E, W, Q, R, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹¹ can be selected from H, P,I, T, H, A, S, F, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹² can be C.

In IL-2Rα ligands of Formula (8a)-(8c), X¹³ can be selected from D, V,L, I, Y, I, R, H, T, I, and W.

In IL-2Rα ligands of Formula (8a)-(8c), X¹⁴ can be selected from T, S,F, and I.

In IL-2Rα ligands of Formula (8a)-(8c), X¹ can be selected from R, I, L,M, N, S, T, V, and D.

In IL-2Rα ligands of Formula (8a)-(8c), X² can be selected from S, K, R,H, G, and F.

In IL-2Rα ligands of Formula (8a)-(8c), X³ can be C.

In IL-2Rα ligands of Formula (8a)-(8c), X⁴ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X⁴ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁵ can be selected from Y, L, E,D, S, I, Y, D, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁶ can be selected from Y, L, E,D, S, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁶ can be selected from D and E.

In IL-2Rα ligands of Formula (8a)-(8c), X⁷ can be selected from G, E, K,T, P, W, L, Y, G, S, and R.

In IL-2Rα ligands of Formula (8a)-(8c), X⁸ can be selected from I, A, Q,R, S R, L, N, P, A, I, R, D, and W.

In IL-2Rα ligands of Formula (8a)-(8c), X⁹ can be selected from W, G, S,D, R, L, F, P, A, and T.

In IL-2Rα ligands of Formula (8a)-(8c), X¹⁰ can be selected from G, T,E, W, Q, R, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹⁰ can be G.

In IL-2Rα ligands of Formula (8a)-(8c), X¹¹ can be selected from H, P,I, T, H, A, S, F, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹² can be C.

In IL-2Rα ligands of Formula (8a)-(8c), X¹³ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (8a)-(8c), X¹⁴ can be F.

In IL-2Rα ligands of Formula (8a)-(8c), X² can be R, X³ can be C, X⁶,can be D, X¹⁰ can be G, X¹² can be C, and X¹⁴ can be F.

In IL-2Rα ligands of Formula (8a)-(8c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be R;

X³ can be C;

X⁴ can be selected from F, H, I, K, L, M, R, V, W, and Y;

X⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁶ can be D;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be G;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be C;

X¹³ can be selected from F, I, L, M, V, W, and Y; and

X¹⁴ can be F.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 72 to SEQ ID NO: 86:

SEQ ID NO: 72 R S C N R Y G I W G H C D T SEQ ID NO: 73I K C R V L E A G T P C V F SEQ ID NO: 74 I R C R Y E K Q S G I C L FSEQ ID NO: 75 L R C R L D T R D G T C R F SEQ ID NO: 76M R C I L S P S R E H C L F SEQ ID NO: 77 N H C T M D W R L G A C I FSEQ ID NO: 78 S G C R L S L L D G H C Y F SEQ ID NO: 79S K C V Y D Y N F G T C I F SEQ ID NO: 80 S R C V M S L Q L G A C I FSEQ ID NO: 81 T R C T V I G P P W S C R F SEQ ID NO: 82V F C I G Y G A A Q S C H S SEQ ID NO: 83 V R C L Y D S I T R T C T FSEQ ID NO: 84 V S C K I D R R S G S C L F SEQ ID NO: 85V S C R F R P D L G F C I F SEQ ID NO: 86 D R C D T R T W G Y Y C W I

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 69 to SEQ ID NO:86.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 69 to SEQ ID NO:86, or a truncated amino acid sequence of any one of SEQ ID NO: 69 toSEQ ID NO: 86, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 69 to SEQ ID NO:86, or a truncated amino acid sequence of any one of SEQ ID NO: 69 toSEQ ID NO: 86, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (9a) (SEQ ID NO: 87), the amino acid sequenceof Formula (9b) (SEQ ID NO: 88), the amino acid sequence of Formula (9c)(SEQ ID NO: 89), or the amino acid sequence of Formula (9d) (SEQ ID NO:90):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (9a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (9b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (9c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (9d)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid comprising a large        hydrophobic side chain or an acidic side chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain;    -   X⁶ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain;    -   X¹¹ can be selected from an amino acid comprising a basic side        chain or an acidic side chain;    -   X¹² can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹³ can be C;    -   X¹⁴ can be selected from an amino acid;    -   X¹⁵ can be selected from an amino acid; and    -   X¹⁶ can be selected from an amino acid.

In IL-2Rα ligands of Formula (9a)-(9d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from F, I, L, M, V, W, and Y;

X³ can be selected from D, E, F, I, L, M, V, W, and Y;

X⁴ can be C;

X⁵ can be selected from F, H, I, K, L, M, R, V, W, and Y;

X⁶ can be selected from F, I, L, M, V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, G, P, S, and T;

X⁹ can be selected from A, G, P, S, and T;

X¹⁰ can be selected from F, H, I, K, L, M, R, V, W, and Y;

X¹¹ can be selected from D, E, H, K, and R;

X¹² can be selected from A, G, H, N, P, Q, S, T, and Y;

X¹³ can be C;

X¹⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y; and

X¹⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹ can be selected from G, E, F,K, P, Q, R, S, and V.

In IL-2Rα ligands of Formula (9a)-(9d), X² can be selected from S, W, I,F, L, and R.

In IL-2Rα ligands of Formula (9a)-(9d), X³ can be selected from R, E, I,V, S, N, F, L, and M.

In IL-2Rα ligands of Formula (9a)-(9d), X⁴ can be C.

In IL-2Rα ligands of Formula (9a)-(9d), X⁵ can be selected from Y, R, V,T, E, I, and K.

In IL-2Rα ligands of Formula (9a)-(9d), X⁶ can be selected from W, F, Y,L, H, I, T, S, and V.

In IL-2Rα ligands of Formula (9a)-(9d), X⁷ can be selected from D, L, S,D, V, Y, S, Q, I, R, M, G, and A.

In IL-2Rα ligands of Formula (9a)-(9d), X⁸ can be P.

In IL-2Rα ligands of Formula (9a)-(9d), X⁹ can be G.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁰ can be selected from R, S,T, N, R, V, L, H, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹¹ can be selected from E, R,H, G, E, K, Q, and V.

In IL-2Rα ligands of Formula (9a)-(9d), X¹² can be selected from V, G,S, A, and W.

In IL-2Rα ligands of Formula (9a)-(9d), X¹³ can be C.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁴ can be selected from I, S,R, W, H, V, K, T, R, G, and P.

In IL-2Rα ligands of Formula (9a)-(9d), X¹³ can be selected from F, L,M, S, W, T, A, and R.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁴ can be selected from K, F,V, I, F, M, L, Q, T, and N.

In IL-2Rα ligands of Formula (9a)-(9d), X¹ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X² can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X³ can be W.

In IL-2Rα ligands of Formula (9a)-(9d), X⁴ can be C.

In IL-2Rα ligands of Formula (9a)-(9d), X⁵ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X⁵ can be selected from D and E.

In IL-2Rα ligands of Formula (9a)-(9d), X⁶ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X⁶ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X⁷ can be selected from A, D, E,F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X⁸ can be P.

In IL-2Rα ligands of Formula (9a)-(9d), X⁹ can be G.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁰ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁰ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁰ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (9a)-(9d), X¹¹ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (9a)-(9d), X¹¹ can be selected from D andE.

In IL-2Rα ligands of Formula (9a)-(9d), X¹² can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (9a)-(9d), X¹² can be selected from N, Q,S, T, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹¹ can be C.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁴ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁵ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁶ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X¹⁶ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (9a)-(9d), X² can be W, X³ can be E, X⁴ canbe C, X⁵, can be R,

X⁸ can be P, X⁹ can be G, X¹⁰ can be R, X¹¹ can be R, X¹² can be G, andX¹¹ can be C.

In IL-2Rα ligands of Formula (9a)-(9d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be W;

X³ can be E;

X⁴ can be C;

X⁵ can be R;

X⁶ can be selected from F, H, I, L, M, V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be P;

X⁹ can be G

X¹⁰ can be R;

X¹¹ can be R;

X¹² can be G;

X¹³ can be C;

X¹⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y; and

X¹⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 91 to SEQ ID NO: 104:

SEQ ID NO: 91 G S R C Y W D P G R E V C I F K SEQ ID NO: 92E W E C R F L P G R R G C S L F SEQ ID NO: 93F W E C V Y S P G S R G C R M V SEQ ID NO: 94G F R C T Y D P G T H S C W S I SEQ ID NO: 95K W I C R L V P G N G A C H S F SEQ ID NO: 96P W V C E H Y P G R R G C V L M SEQ ID NO: 97Q W S C V F S P G V R G C K L V SEQ ID NO: 98R F I C R I Q P G R E G C W S L SEQ ID NO: 99R W E C I Y I P G R K G C T L Q SEQ ID NO: 100S L N C K T R P G L R W C T W T SEQ ID NO: 101S W E C V Y M P G H Q G C L R F SEQ ID NO: 102V R F C R S G P G W V S C G T Q SEQ ID NO: 103V R L C R V G P G Y E S C P A N SEQ ID NO: 104V R M C Y V A P G Y V S C P R M

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 87 to SEQ ID NO:104.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 87 to SEQ ID NO:104, or a truncated amino acid sequence of any one of SEQ ID NO: 87 toSEQ ID NO: 104, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 87 to SEQ ID NO:104, or a truncated amino acid sequence of any one of SEQ ID NO: 87 toSEQ ID NO: 104, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (10a) (SEQ ID NO: 105), the amino acid sequenceof Formula (10b) (SEQ ID NO: 106), the amino acid sequence of Formula(10c) (SEQ ID NO: 107), or the amino acid sequence of Formula (10d) (SEQID NO: 108):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (10a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (10b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (10c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (10d)

wherein,

-   -   X¹ can be selected from an amino acid comprising an acidic side        chain;    -   X² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X³ can be selected from an amino acid comprising an acidic side        chain;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁷ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁸ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid comprising a basic side        chain;    -   X¹¹ can be selected from an amino acid comprising a basic side        chain;    -   X¹² can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹³ can be C;    -   X¹⁴ can be selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (10a)-(10d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from F, I, L, M, V, W, and Y;

X³ can be selected from D and E;

X⁴ can be C;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from F, I, L, M, V, W, and Y;

X⁷ can be selected from F, I, L, M, V, W, and Y;

X⁸ can be selected from A, G, P, S, and T;

X⁹ can be selected from A, G, P, S, and T;

X¹⁰ can be selected from H, K, and R;

X¹¹ can be selected from H, K, and R;

X¹² can be selected from A, G, P, S, and T;

X¹³ can be C;

X¹⁴ can be selected from A, G, H, N, P, Q, S, T, and Y;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (10a)-(10d), X¹ can be selected from N, D,E, A, V, and T.

In IL-2Rα ligands of Formula (10a)-(10d), X² can be selected from W andY.

In IL-2Rα ligands of Formula (10a)-(10d), X³ can be selected from E, H,and D.

In IL-2Rα ligands of Formula (10a)-(10d), X⁴ can be C.

In IL-2Rα ligands of Formula (10a)-(10d), X⁵ can be selected from I, l,W, and V.

In IL-2Rα ligands of Formula (10a)-(10d), X⁶ can be selected from F andI.

In IL-2Rα ligands of Formula (10a)-(10d), X⁷ can be selected from S, L,and M.

In IL-2Rα ligands of Formula (10a)-(10d), X⁸ can be P.

In IL-2Rα ligands of Formula (10a)-(10d), X⁹ can be G.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁰ can be selected from R andH.

In IL-2Rα ligands of Formula (10a)-(10d), X¹¹ can be selected from R andK.

In IL-2Rα ligands of Formula (10a)-(10d), X¹² can be G.

In IL-2Rα ligands of Formula (10a)-(10d), X¹³ can be C.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁴ can be selected from S, L,T, and F.

In IL-2Rα ligands of Formula (10a)-(10d), X¹³ can be selected from L andG.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁴ can be selected from F, M,T, and I.

In IL-2Rα ligands of Formula (10a)-(10d), X¹ can be selected from D andE.

In IL-2Rα ligands of Formula (10a)-(10d), X² can be W.

In IL-2Rα ligands of Formula (10a)-(10d), X³ can be selected from D andE.

In IL-2Rα ligands of Formula (10a)-(10d), X⁴ can be C.

In IL-2Rα ligands of Formula (10a)-(10d), X⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (10a)-(10d), X⁵ can be selected from I andL.

In IL-2Rα ligands of Formula (10a)-(10d), X⁶ can be F.

In IL-2Rα ligands of Formula (10a)-(10d), X⁷ can be selected from L andM.

In IL-2Rα ligands of Formula (10a)-(10d), X⁸ can be P.

In IL-2Rα ligands of Formula (10a)-(10d), X⁹ can be G.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁰ can be selected from H andR.

In IL-2Rα ligands of Formula (10a)-(10d), X¹¹ can be selected from K andR.

In IL-2Rα ligands of Formula (10a)-(10d), X¹² can be G.

In IL-2Rα ligands of Formula (10a)-(10d), X¹³ can be C.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁴ can be selected from S andT.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁵ can be L.

In IL-2Rα ligands of Formula (10a)-(10d), X¹⁶ can be selected from F andM.

In IL-2Rα ligands of Formula (10a)-(10d),

X¹ can be D;

X² can be W;

X³ can be E;

X⁴ can be C;

X⁵ can be L;

X⁶ can be F;

X⁷ can be L;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from H and R;

X¹¹ can be selected from K and R;

X¹² can be G;

X¹³ can be C;

X¹⁴ can be T;

X¹⁵ can be L; and

X¹⁶ can be F.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 109 to SEQ ID NO: 121:

SEQ ID NO: 109 N W E C I F S P G R R G C S L T SEQ ID NO: 110D W E C L F L P G R R G C L L F SEQ ID NO: 111E W E C L F M P G R R G C L L M SEQ ID NO: 112A W E C L F L P G H R G C S L F SEQ ID NO: 113E W E C L F L P G R K G C T L F SEQ ID NO: 114D W E C I F L P G R R G C T L F SEQ ID NO: 115V Y E C L F M P G R K G CF G M SEQ ID NO: 116E W E C W F L P G R R G C T L I SEQ ID NO: 117D W H C L F L P G H R G C T L F SEQ ID NO: 118D W E C L F L P G R R G C T L F SEQ ID NO: 119Y W E C V F M P G H R G C S L I SEQ ID NO: 120T W D C L F L P G R R G C T L M SEQ ID NO: 121N W E C I F S P G R R G C S L T

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 105 to SEQ ID NO:121.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 105 to SEQ IDNO: 121, or a truncated amino acid sequence of any one of SEQ ID NO: 105to SEQ ID NO: 121, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 105 to SEQ IDNO: 121, or a truncated amino acid sequence of any one of SEQ ID NO: 105to SEQ ID NO: 121, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (11a) (SEQ ID NO: 122), the amino acid sequenceof Formula (11b) (SEQ ID NO: 123), the amino acid sequence of Formula(11c) (SEQ ID NO: 124), or the amino acid sequence of Formula (11d) (SEQID NO: 125):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (11a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (11b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (11c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (11d)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid;    -   X³ can be selected from an amino acid;    -   X⁴ can be C;    -   X⁵ can be selected from an amino acid comprising an acidic side        chain;    -   X⁶ can be selected from an amino acid    -   X⁷ can be selected from an amino acid comprising an acidic side        chain or an aromatic side chain;    -   X⁸ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid comprising an aromatic        chain;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid;    -   X¹³ can be C;    -   X¹⁴ can be selected from an amino acid;    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (11a)-(11d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁴ can be C;

X⁵ can be selected from D and E;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from D, E, F, H, W, and Y;

X⁸ can be selected from A, G, P, S, and T;

X⁹ can be selected from A, G, P, S, and T;

X¹⁰ can be selected from F, H, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be C;

X¹⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (11a)-(11d), X¹ can be selected from A, E,F, G, K, R, T, Y, and W.

In IL-2Rα ligands of Formula (11a)-(11d), X² can be selected from G, T,K, Q, S, L, Q, R, and A.

In IL-2Rα ligands of Formula (11a)-(11d), X³ can be selected from F, Y,W, and H.

In IL-2Rα ligands of Formula (11a)-(11d), X³ can be selected from G, W,P, L, R, F, M, V, S, and P.

In IL-2Rα ligands of Formula (11a)-(11d), X⁴ can be C.

In IL-2Rα ligands of Formula (11a)-(11d), X⁵ can be selected from K, D,Y, T, Y, Q, F, L, and S.

In IL-2Rα ligands of Formula (11a)-(11d), X⁶ can be selected from L, D,F, Y, W, N, D, M, V, D, L, and Y.

In IL-2Rα ligands of Formula (11a)-(11d), X⁷ can be selected from N, H,F, D, N, S, L, and Y.

In IL-2Rα ligands of Formula (11a)-(11d), X⁸ can be P.

In IL-2Rα ligands of Formula (11a)-(11d), X⁹ can be G.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁰ can be selected from T, H,L, S, Q, R, N, Y, W, V, S, and H.

In IL-2Rα ligands of Formula (11a)-(11d), X¹¹ can be selected from Q, W,P, D, E, S, P, E, H, G, R, and G.

In IL-2Rα ligands of Formula (11a)-(11d), X¹² can be selected from V, S,R, I, A, D, S, E, Y, and G.

In IL-2Rα ligands of Formula (11a)-(11d), X¹³ can be C.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁴ can be selected from S, E,T, V, I, D, Q, W, P, I, and Y.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁵ can be selected from F, M,W, I, V, T, N, L, and S.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁶ can be selected from Y, V,I, L, S, K, E, and R.

In IL-2Rα ligands of Formula (11a)-(11d), X⁴ can be C.

In IL-2Rα ligands of Formula (11a)-(11d), X⁵ can be D.

In IL-2Rα ligands of Formula (11a)-(11d), X⁷ can be selected from D andH.

In IL-2Rα ligands of Formula (11a)-(11d), X⁸ can be P.

In IL-2Rα ligands of Formula (11a)-(11d), X⁹ can be G.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁰ can be selected from F, H,W, and Y.

In IL-2Rα ligands of Formula (11a)-(11d), X¹³ can be C.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁵ can be selected from F, M,I, W, V, and L.

In IL-2Rα ligands of Formula (11a)-(11d), X¹⁶ can be selected from Y, V,I, and L.

In IL-2Rα ligands of Formula (11a)-(11d),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁴ can be C;

X⁵ can be selected from D and E;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from D, E, H, F, W, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from H, F, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be C;

X¹⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 126 to SEQ ID NO: 140:

SEQ ID NO: 126 A G W C K L N P G T Q V C S F Y SEQ ID NO: 127E T P C D L H P G H W S C S M V SEQ ID NO: 128F F L C D D F P G L P R C E W I SEQ ID NO: 129G L R C Y F D P G S Q I C T F L SEQ ID NO: 130G Q R C T Y D P G Q D A C V F S SEQ ID NO: 131G S R C Y W D P G R E V C I I F SEQ ID NO: 132K L W C Q N N P G N S I C D M Y SEQ ID NO: 133K S W C F D H P G Y P I C Q F Y SEQ ID NO: 134R L F C L M N P G P P D C W I Y SEQ ID NO: 135R Q F C L V S P G Y E D C W F V SEQ ID NO: 136T R M C F D D P G W H S C P V V SEQ ID NO: 137T R W C S L H P G V G E C V T L SEQ ID NO: 138T T V C D Y H P G S R Y C I N E SEQ ID NO: 139Y A S C T Y L P G H R G C T L V SEQ ID NO: 140W L P C D D Y P G H G Y C Y S R

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 122 to SEQ ID NO:140.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 122 to SEQ IDNO: 140, or a truncated amino acid sequence of any one of SEQ ID NO: 122to SEQ ID NO: 140, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 122 to SEQ IDNO: 140, or a truncated amino acid sequence of any one of SEQ ID NO: 122to SEQ ID NO: 140, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (12a) (SEQ ID NO: 141), the amino acid sequenceof Formula (12b) (SEQ ID NO: 142), or the amino acid sequence of Formula(12c) (SEQ ID NO: 143):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (12a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (12b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (12c)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid;    -   X³ can be C;    -   X⁴ can be selected from an amino acid;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid comprising an acidic side        chain, a small hydrophobic side chain, or a polar neutral side        chain;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹³ can be C;    -   X¹⁴ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ can be selected from an amino acid.

In IL-2Rα ligands of Formula (12a)-(12c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, G, H, N, P, Q, S, T, and Y;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from F, I, L, M, V, W, and Y;

X¹² can be selected from F, I, L, M, V, W, and Y;

X¹³ can be C;

X¹⁴ can be selected from F, I, L, M, V, W, and Y; and

X¹⁵ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X¹ can be selected from S, N,Q, R, and G.

In IL-2Rα ligands of Formula (12a)-(12c), X² can be selected from A, H,R, and G.

In IL-2Rα ligands of Formula (12a)-(12c), X³ can be C.

In IL-2Rα ligands of Formula (12a)-(12c), X⁴ can be selected from Q, T,N, M, and S.

In IL-2Rα ligands of Formula (12a)-(12c), X⁵ can be selected from L andR.

In IL-2Rα ligands of Formula (12a)-(12c), X⁶ can be selected from K, S,R, and V.

In IL-2Rα ligands of Formula (12a)-(12c), X⁷ can be selected from W, K,and L.

In IL-2Rα ligands of Formula (12a)-(12c), X⁸ can be selected from D, T,L, Q, and A.

In IL-2Rα ligands of Formula (12a)-(12c), X⁹ can be selected from E, Y,D, and P.

In IL-2Rα ligands of Formula (12a)-(12c), X¹⁰ can be selected from G, P,A, E, and S.

In IL-2Rα ligands of Formula (12a)-(12c), X¹¹ can be selected from W andL.

In IL-2Rα ligands of Formula (12a)-(12c), X¹² can be selected from T, V,I, and A.

In IL-2Rα ligands of Formula (12a)-(12c), X¹³ can be C.

In IL-2Rα ligands of Formula (12a)-(12c), X¹⁴ can be selected from L, V,Q, and I.

In IL-2Rα ligands of Formula (12a)-(12c), X¹³ can be selected from F andA.

In IL-2Rα ligands of Formula (12a)-(12c), X¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X³ can be C.

In IL-2Rα ligands of Formula (12a)-(12c), X⁴ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X⁵ can be L.

In IL-2Rα ligands of Formula (12a)-(12c), X⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X⁷ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X⁹ can be selected from D andE.

In IL-2Rα ligands of Formula (12a)-(12c), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X¹¹ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X¹¹ can be W.

In IL-2Rα ligands of Formula (12a)-(12c), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X¹³ can be C.

In IL-2Rα ligands of Formula (12a)-(12c), X¹⁴ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (12a)-(12c), X¹⁵ can be F.

In IL-2Rα ligands of Formula (12a)-(12c), X³ can be C, X⁵ can be L, X⁹can be D or E, X¹¹ can be W, X¹³ can be C, and X¹⁵ can be F.

In IL-2Rα ligands of Formula (12a)-(12c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁵ can be L;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from D and E;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y:

X¹¹ can be selected from F, I, L, M, V, W, and Y;

X¹² can be selected from F, I, L, M, V, W, and Y;

X¹³ can be C;

X¹⁴ can be selected from F, I, L, M, V, W, and Y; and

X¹⁵ can be F.

In IL-2Rα ligands of Formula (12a)-(12c), X³ can be C, X⁵ can be L, X¹¹can be W, X¹³ can be C, and X¹⁵ can be F.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 144 to SEQ ID NO: 148:

SEQ ID NO: 144 S A C Q L K W D E G W T C L F SEQ ID NO: 145N H C T L S K T Y P W V C V F SEQ ID NO: 146Q R C N R S L L D A L I C Q A SEQ ID NO: 147R G C M L R L Q P E L A C V F SEQ ID NO: 148G G C S L V W A D S W V C I F

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 141 to SEQ ID NO:148.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 141 to SEQ IDNO: 148, or a truncated amino acid sequence of any one of SEQ ID NO: 141to SEQ ID NO: 148, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 141 to SEQ IDNO: 148, or a truncated amino acid sequence of any one of SEQ ID NO: 141to SEQ ID NO: 148, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (13a) (SEQ ID NO: 149), the amino acid sequenceof Formula (13b) (SEQ ID NO: 150), or the amino acid sequence of Formula(13c) (SEQ ID NO: 151):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (13a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (13b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (13c)

wherein,

-   -   X¹ can be selected from an amino acid comprising a small        hydrophobic side chain or a basic side chain;    -   X² can be selected from an amino acid comprising a small        hydrophobic side chain or a basic side chain;    -   X³ can be C;    -   X⁴ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁷ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid comprising an acidic side        chain;    -   X¹⁰ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain or an acidic side chain;    -   X¹³ can be C;    -   X¹⁴ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (13a)-(13c),

X¹ can be selected from A, G, H, K, P, R, S, and T;

X² can be selected from A, G, H, K, P, R, S, and T;

X³ can be C;

X⁴ can be selected from A, G, P, S, and T;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from F, I, L, M, V, W, and Y;

X⁷ can be selected from F, I, L, M, V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from D and E;

X¹⁰ can be selected from A, G, P, S, and T;

X¹¹ can be selected from F, I, L, M, V, W, and Y;

X¹² can be selected from D, E, F, I, L, M, V, W, and Y;

X¹³ can be C;

X¹⁴ can be selected from F, I, L, M, V, W, and Y; and

X¹⁵ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X¹ can be selected from S, R,Q, V, A, and G.

In IL-2Rα ligands of Formula (13a)-(13c), X² can be selected from R, G,A, and S.

In IL-2Rα ligands of Formula (13a)-(13c), X³ can be C.

In IL-2Rα ligands of Formula (13a)-(13c), X⁴ can be selected from S, T,Q, and H.

In IL-2Rα ligands of Formula (13a)-(13c), X⁵ can be L.

In IL-2Rα ligands of Formula (13a)-(13c), X⁶ can be selected from V, Q,A, and R.

In IL-2Rα ligands of Formula (13a)-(13c), X⁷ can be selected from W andF.

In IL-2Rα ligands of Formula (13a)-(13c), X⁸ can be selected from T, D,S, L, A, E, and Q.

In IL-2Rα ligands of Formula (13a)-(13c), X⁹ can be selected from D, G,and E.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁰ can be selected from T, S,R, G, A, S, and N.

In IL-2Rα ligands of Formula (13a)-(13c), X¹¹ can be W.

In IL-2Rα ligands of Formula (13a)-(13c), X¹² can be selected from V andE.

In IL-2Rα ligands of Formula (13a)-(13c), X¹³ can be C.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁴ can be selected from V andI.

In IL-2Rα ligands of Formula (13a)-(13c), X¹³ can be F.

In IL-2Rα ligands of Formula (13a)-(13c), X¹ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (13a)-(13c), X¹ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (13a)-(13c), X² can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (13a)-(13c), X² can be selected from H, K,and R.

In IL-2Rα ligands of Formula (13a)-(13c), X² can be selected from R andG.

In IL-2Rα ligands of Formula (13a)-(13c), X³ can be C.

In IL-2Rα ligands of Formula (13a)-(13c), X⁴ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (13a)-(13c), X⁴ can be selected from S andT.

In IL-2Rα ligands of Formula (13a)-(13c), X⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X⁵ can be L.

In IL-2Rα ligands of Formula (13a)-(13c), X⁶ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X⁶ can be V.

In IL-2Rα ligands of Formula (13a)-(13c), X⁷ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X⁷ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X⁷ can be W.

In IL-2Rα ligands of Formula (13a)-(13c), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X⁸ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (13a)-(13c), X⁸ can be A.

In IL-2Rα ligands of Formula (13a)-(13c), X⁹ can be selected from D andE.

In IL-2Rα ligands of Formula (13a)-(13c), X⁹ can be D.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁰ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁰ can be S.

In IL-2Rα ligands of Formula (13a)-(13c), X¹¹ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X¹¹ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X¹¹ can be W.

In IL-2Rα ligands of Formula (13a)-(13c), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X¹² can be selected from D andE.

In IL-2Rα ligands of Formula (13a)-(13c), X¹² can be selected from V andE.

In IL-2Rα ligands of Formula (13a)-(13c), X¹² can be V.

In IL-2Rα ligands of Formula (13a)-(13c), X¹³ can be C.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁴ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁴ can be I.

In IL-2Rα ligands of Formula (13a)-(13c), X¹⁵ can be F.

In IL-2Rα ligands of Formula (13a)-(13c), X² can be R, X³ can be C, X⁵can be S, X⁶ can be L, X⁷ can be V, X⁸ can be W, X¹⁰ can be D, X¹¹ canbe S, X¹² can be W, X¹¹ can be V, X¹⁴ can be C, X¹⁵ can be I, and X¹⁶can be F.

In IL-2Rα ligands of Formula (13a)-(13c),

X¹ can be selected from A, D, E, G, P, S, and T;

X² can be selected from G and R;

X³ can be C;

X⁴ can be selected from S and T;

X⁵ can be L;

X⁶ can be V;

X⁷ can be selected from F and W;

X⁸ can be selected from A, G, P, S, and T;

X⁹ can be selected from D and E;

X¹⁰ can be S;

X¹¹ can be W;

X¹² can be V;

X¹³ can be C;

X¹⁴ can be I; and

X¹⁵ can be F.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 152 to SEQ ID NO: 166:

SEQ ID NO: 152 S R C S L V W T D T W V C V F SEQ ID NO: 153 S R C T L VF D D S W V C V F SEQ ID NO: 154 R G C S L V W S G S W E C I FSEQ ID NO: 155 Q A C Q L V W L D S W V C I F SEQ ID NO: 156 V G C S L VW T D R W E C I F SEQ ID NO: 157 S G C S L Q W A D G W V C I FSEQ ID NO: 158 A R C S L V W D E A W V C I F SEQ ID NO: 159 R G C S L VW A G S W E C I F SEQ ID NO: 160 S R C S L V W A E N W V C I FSEQ ID NO: 161 R R C T L V F L D S W E C I F SEQ ID NO: 162 R G C T L AW E D S W V C I F SEQ ID NO: 163 R G C S L R F A E A W E C I FSEQ ID NO: 164 A S C S L V W Q D S W V C I F SEQ ID NO: 165 S R C S L VW A D S W V C I F SEQ ID NO: 166 G R C H L V W S D R W E C I F

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 149 to SEQ ID NO:166.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 149 to SEQ IDNO: 166, or a truncated amino acid sequence of any one of SEQ ID NO: 149to SEQ ID NO: 166, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 149 to SEQ IDNO: 166, or a truncated amino acid sequence of any one of SEQ ID NO: 149to SEQ ID NO: 166, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (14a) (SEQ ID NO: 167), or the amino acidsequence of Formula (14b) (SEQ ID NO: 168):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (14a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (14b)

wherein,

-   -   X¹ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X² can be C;    -   X³ can be selected from an amino acid comprising a small        hydrophobic side chain;    -   X⁴ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁵ can be selected from an amino acid;    -   X⁶ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁷ can be selected from an amino acid comprising an acidic side        chain or a polar neutral side chain;

X⁸ can be selected from an amino acid;

X⁹ can be selected from an amino acid;

X¹⁰ can be selected from an amino acid comprising a large hydrophobicside chain;

X¹¹ can be selected from an amino acid comprising a large hydrophobicside chain;

X¹² can be selected from an amino acid comprising a large hydrophobicside chain or an acidic side chain;

X¹³ can be C; and

X¹⁴ can be selected from an amino acid comprising a large hydrophobicside chain.

In IL-2Rα ligands of Formula (14a)-(14b),

X¹ can be selected from A, G, P, S, and T;

X² can be C;

X³ can be selected from A, G, P, S, and T;

X⁴ can be selected from F, I, L, M, V, W, and Y;

X⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁶ can be selected from F, I, L, M, V, W, and Y;

X⁷ can be selected from D, E, N, Q, S, T, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be selected from F, I, L, M, V, W, and Y;

X¹¹ can be selected from F, I, L, M, V, W, and Y;

X¹² can be selected from D, E, F, I, L, M, V, W, and Y;

X¹³ can be C; and

X¹⁴ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X¹ can be selected from G andS.

In IL-2Rα ligands of Formula (14a)-(14b), X² can be C.

In IL-2Rα ligands of Formula (14a)-(14b), X³ can be selected from T, S,M, and V.

In IL-2Rα ligands of Formula (14a)-(14b), X⁴ can be selected from L andV.

In IL-2Rα ligands of Formula (14a)-(14b), X⁵ can be selected from K, R,M, S, T, and Q.

In IL-2Rα ligands of Formula (14a)-(14b), X⁶ can be selected from W, R,and F.

In IL-2Rα ligands of Formula (14a)-(14b), X⁷ can be selected from E, D,Q, N, G, and S.

In IL-2Rα ligands of Formula (14a)-(14b), X⁸ can be selected from S, G,D, Q, K, and G.

In IL-2Rα ligands of Formula (14a)-(14b), X⁹ can be selected from P, D,G, F, and V.

In IL-2Rα ligands of Formula (14a)-(14b), X¹⁰ can be selected from N andW.

In IL-2Rα ligands of Formula (14a)-(14b), X¹¹ can be W.

In IL-2Rα ligands of Formula (14a)-(14b), X¹² can be selected from T, V,H, and E.

In IL-2Rα ligands of Formula (14a)-(14b), X¹³ can be C.

In IL-2Rα ligands of Formula (14a)-(14b), X¹⁴ can be selected from Y, E,I, and V.

In IL-2Rα ligands of Formula (14a)-(14b), X¹ can be G.

In IL-2Rα ligands of Formula (14a)-(14b), X² can be C.

In IL-2Rα ligands of Formula (14a)-(14b), X³ can be selected from S andT.

In IL-2Rα ligands of Formula (14a)-(14b), X³ can be T.

In IL-2Rα ligands of Formula (14a)-(14b), X⁴ can be L.

In IL-2Rα ligands of Formula (14a)-(14b), X⁵ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X⁶ can be W.

In IL-2Rα ligands of Formula (14a)-(14b), X⁷ can be selected from D, E,Q, and N.

In IL-2Rα ligands of Formula (14a)-(14b), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X⁹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X¹⁰ can be W.

In IL-2Rα ligands of Formula (14a)-(14b), X¹¹ can be W.

In IL-2Rα ligands of Formula (14a)-(14b), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X¹² can be selected from D andE.

In IL-2Rα ligands of Formula (14a)-(14b), X¹² can be selected from E andV.

In IL-2Rα ligands of Formula (14a)-(14b), X¹³ can be C.

In IL-2Rα ligands of Formula (14a)-(14b), X¹⁴ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (14a)-(14b), X¹⁴ can be selected from I andV.

In IL-2Rα ligands of Formula (14a)-(14b), X¹ can be G, X² can be C, X³can be T, X⁴ can be L, X⁶ can be W, X¹⁰ can be W, X¹¹ can be W, and X¹¹can be C.

In IL-2Rα ligands of Formula (14a)-(14b),

X¹ can be G;

X² can be C;

X³ can be selected from T and S;

X⁴ can be L;

X⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁶ can be W;

X⁷ can be selected from D, E, N, Q, S, T, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be W;

X¹¹ can be W;

X¹² can be selected from V and E;

X¹³ can be C; and

X¹⁴ can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 169 to SEQ ID NO: 174:

SEQ ID NO: 169 G C T L K W E S P N W T C Y SEQ ID NO: 170 S C T V R W DG D W W V C E SEQ ID NO: 171 G C S L M W Q D G W W V C I SEQ ID NO: 172G C T L S W N Q G W W H C V SEQ ID NO: 173 G C M L T R G K F W W E C ISEQ ID NO: 174 G C V L Q F S G V W W E C V

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 167 to SEQ ID NO:174.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 167 to SEQ IDNO: 174, or a truncated amino acid sequence of any one of SEQ ID NO: 167to SEQ ID NO: 174, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 167 to SEQ IDNO: 174, or a truncated amino acid sequence of any one of SEQ ID NO: 167to SEQ ID NO: 174, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (15a) (SEQ ID NO: 175), the amino acid sequenceof Formula (15b) (SEQ ID NO: 176), or the amino acid sequence of Formula(15c) (SEQ ID NO: 177):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (15a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (15b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—X¹⁶—  (15c)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid;    -   X³ can be C;    -   X⁴ can be selected from an amino acid comprising a polar/neutral        side chain or a basic side chain;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid comprising a polar neutral        side chain or a basic side chain;    -   X⁸ can be P;    -   X⁹ can be G;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹³ can be selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X¹⁴ can be C;    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (15a)-(15c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from H, K, N, Q, R, S, T, and Y;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from H, K, N, Q, R, S, T, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from F, I, L, M, V, W, and Y;

X¹³ can be selected from D, E, N, Q, S, T, and Y;

X¹⁴ can be C;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X¹ can be selected from Q, A,G, K, L, N, P, Q, S, and T.

In IL-2Rα ligands of Formula (15a)-(15c), X² can be selected from R, G,K, T, P, A, S, and H.

In IL-2Rα ligands of Formula (15a)-(15c), X³ can be C.

In IL-2Rα ligands of Formula (15a)-(15c), X⁴ can be selected from Q, M,S, R, T, I, K, R, H, and L.

In IL-2Rα ligands of Formula (15a)-(15c), X⁵ can be selected from L, P,M, and V.

In IL-2Rα ligands of Formula (15a)-(15c), X⁶ can be selected from S, L,R, Q, F, W, N, I, and G.

In IL-2Rα ligands of Formula (15a)-(15c), X⁷ can be selected from K, H,R, W, L, N, F, and V.

In IL-2Rα ligands of Formula (15a)-(15c), X⁸ can be selected from S, P,T, and L.

In IL-2Rα ligands of Formula (15a)-(15c), X⁹ can be G.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁰ can be selected from G, L,S, D, T, E, M, N, F, H, R, K, and P.

In IL-2Rα ligands of Formula (15a)-(15c), X¹¹ can be selected from E, Y,R, G, H, S, I, G, L, W, F, and V.

In IL-2Rα ligands of Formula (15a)-(15c), X¹² can be selected from L, W,Y, H, and V.

In IL-2Rα ligands of Formula (15a)-(15c), X¹³ can be selected from G, E,V, T, Q, and A.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁵ can be selected from M, I,V, L, W, R, and F.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁶ can be selected from F, S,and G.

In IL-2Rα ligands of Formula (15a)-(15c), X¹ can be selected from S andT.

In IL-2Rα ligands of Formula (15a)-(15c), X² can be selected from S, T,R, and K.

In IL-2Rα ligands of Formula (15a)-(15c), X³ can be C.

In IL-2Rα ligands of Formula (15a)-(15c), X⁴ can be selected from N, Q,S, T, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X⁴ can be T.

In IL-2Rα ligands of Formula (15a)-(15c), X⁵ can be selected from L, M,and V.

In IL-2Rα ligands of Formula (15a)-(15c), X⁵ can be L.

In IL-2Rα ligands of Formula (15a)-(15c), X⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X⁷ can be selected from N, K,H, and R.

In IL-2Rα ligands of Formula (15a)-(15c), X⁷ can be N.

In IL-2Rα ligands of Formula (15a)-(15c), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X⁸ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (15a)-(15c), X⁸ can be P.

In IL-2Rα ligands of Formula (15a)-(15c), X⁹ can be G.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X¹¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X¹¹ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (15a)-(15c), X¹¹ can be G.

In IL-2Rα ligands of Formula (15a)-(15c), X¹² can be W.

In IL-2Rα ligands of Formula (15a)-(15c), X¹³ can be selected from N, Q,S, T, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X¹³ can be selected from D andE.

In IL-2Rα ligands of Formula (15a)-(15c), X¹³ can be selected from E andQ.

In IL-2Rα ligands of Formula (15a)-(15c), X¹³ can be E.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁵ can be selected from M, I,V, L, and F.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁵ can be selected from I andV.

In IL-2Rα ligands of Formula (15a)-(15c), X¹⁶ can be F.

In IL-2Rα ligands of Formula (15a)-(15c), X³ can be C, X⁵ can be L, X⁸can be P, X⁹ can be G, X¹² can be W, X¹³ can be E, X¹⁴ can be C, and X¹⁶can be F.

In IL-2Rα ligands of Formula (15a)-(15c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from N, Q, S, T, and Y;

X⁵ can be L;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from N, Q, S, T, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, G, P, S, and T;

X¹² can be W;

X¹³ can be selected from E and Q;

X¹⁴ can be C;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be F.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 178 to SEQ ID NO: 195:

SEQ ID NO: 178 Q R C Q L S W S G G E L G C M F SEQ ID NO: 179 A G C M LL K P G L Y W E C I F SEQ ID NO: 180 A R C S L H H T G S R Y E C I FSEQ ID NO: 181 A T C M L R L L G D G W G C V F SEQ ID NO: 182 G P C R LS N P G T G W E C I F SEQ ID NO: 183 K G C T L Q N P G S G W V C L FSEQ ID NO: 184 L A C I L S K P G E H W E C L F SEQ ID NO: 185 N G C T SF S S G M S W T C V Y SEQ ID NO: 186 N S C I L S N P G L G W Q C V FSEQ ID NO: 187 N T C K L F R S G N I W Q C I F SEQ ID NO: 188 P S C R LW N P G F G W E C I F SEQ ID NO: 189 Q S C T L Q R L G H L Y Q C W FSEQ ID NO: 190 S A C T P N W T G R W W E C V F SEQ ID NO: 191 S K C H LI V S G K F H E C V F SEQ ID NO: 192 S S C T L F N P G T G W T C V FSEQ ID NO: 193 S T C R M G N P G G V W G C Y F SEQ ID NO: 194 T H C L VQ W P G P V V A C R S SEQ ID NO: 195 T R C R L L K L G S L W E C F G

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 175 to SEQ ID NO:195.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 175 to SEQ IDNO: 195, or a truncated amino acid sequence of any one of SEQ ID NO: 175to SEQ ID NO: 195, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 175 to SEQ IDNO: 195, or a truncated amino acid sequence of any one of SEQ ID NO: 175to SEQ ID NO: 195, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (16a) (SEQ ID NO: 196), or the amino acidsequence of Formula (16b) (SEQ ID NO: 197):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (16a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (16b)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be C;    -   X³ can be selected from an amino acid comprising a basic side        chain;    -   X⁴ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁵ can be selected from an amino acid comprising a basic side        chain or a polar/neutral side chain;    -   X⁶ can be selected from an amino acid comprising a basic side        chain or a polar/neutral side chain;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X¹³ can be selected from an amino acid comprising an acidic side        chain;    -   X¹⁴ can be C; and    -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (16a)-(16b),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from C;

X³ can be selected from H, K, and R;

X⁴ can be selected from F, I, L, M, V, W, and Y;

X⁵ can be selected from H, K, N, Q, R, S, T, and Y;

X⁶ can be selected from H, K, N, Q, R, S, T, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from F, H, I, L, M, V, W, and Y;

X¹³ can be selected from D and E;

X¹⁴ can be C; and

X¹⁵ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹ can be selected from A, K,N, R, and T.

In IL-2Rα ligands of Formula (16a)-(16b), X² can be C.

In IL-2Rα ligands of Formula (16a)-(16b), X³ can be selected from W, R,and T.

In IL-2Rα ligands of Formula (16a)-(16b), X⁴ can be selected from R, L,and V.

In IL-2Rα ligands of Formula (16a)-(16b), X⁵ can be selected from S, R,Q, K, and H.

In IL-2Rα ligands of Formula (16a)-(16b), X⁶ can be selected from W, Q,H, K, F, and R.

In IL-2Rα ligands of Formula (16a)-(16b), X⁷ can be selected from R, M,L, A, D, S, and I.

In IL-2Rα ligands of Formula (16a)-(16b), X⁸ can be selected from Y, S,P, G, and A.

In IL-2Rα ligands of Formula (16a)-(16b), X⁹ can be selected from P, R,Y, G, Q, P, and L.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁰ can be selected from T, G,P, N, T, N, and A.

In IL-2Rα ligands of Formula (16a)-(16b), X¹¹ can be selected from R, G,F, T, G, S, and E.

In IL-2Rα ligands of Formula (16a)-(16b), X¹² can be selected from T andW.

In IL-2Rα ligands of Formula (16a)-(16b), X¹³ can be selected from F, E,and S.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁴ can be C.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁵ can be selected from S, L,N, I, and V.

In IL-2Rα ligands of Formula (16a)-(16b), X² can be C.

In IL-2Rα ligands of Formula (16a)-(16b), X³ can be R.

In IL-2Rα ligands of Formula (16a)-(16b), X⁴ can be selected from L andV.

In IL-2Rα ligands of Formula (16a)-(16b), X⁵ can be selected from R, K,and H.

In IL-2Rα ligands of Formula (16a)-(16b), X⁶ can be selected from R, K,and H.

In IL-2Rα ligands of Formula (16a)-(16b), X⁷ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X⁸ can be G.

In IL-2Rα ligands of Formula (16a)-(16b), X⁹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹² can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹² can be W.

In IL-2Rα ligands of Formula (16a)-(16b), X¹³ can be E.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁴ can be C.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (16a)-(16b), X¹⁵ can be selected from L, I,and V.

In IL-2Rα ligands of Formula (16a)-(16b), X² can be C, X³ can be R, X¹²can be W, X¹¹ can be E, and X¹⁴ can be C.

In IL-2Rα ligands of Formula (16a)-(16b),

X² can be C;

X³ can be R;

X⁴ can be selected from F, I, L, M, V, W, and Y;

X⁵ can be selected from N, Q, S, T, and Y;

X⁶ can be selected from N, Q, S, T, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, G, P, S, and T;

X⁹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be W;

X¹³ can be E;

X¹⁴ can be C; and

X¹⁵ can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 189 to SEQ ID NO: 204:

SEQ ID NO: 198 A C W R S W R Y P T R T F C S SEQ ID NO: 199 K C R L R QM S R G G W E C L SEQ ID NO: 200 N C R V R H L P Y P F W S C LSEQ ID NO: 201 R C R L Q K A G G N T W E C I SEQ ID NO: 202 R C T L R FD A Q T G W E C N SEQ ID NO: 203 T C R L K R S G P N S W E C ISEQ ID NO: 204 T C T V H R I G L A E W E C V

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 196 to SEQ ID NO:204.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 196 to SEQ IDNO: 204, or a truncated amino acid sequence of any one of SEQ ID NO: 196to SEQ ID NO: 204, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 196 to SEQ IDNO: 204, or a truncated amino acid sequence of any one of SEQ ID NO: 196to SEQ ID NO: 204, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (17a) (SEQ ID NO: 205), the amino acid sequenceof Formula (17b) (SEQ ID NO: 206), or the amino acid sequence of Formula(17c) (SEQ ID NO: 207):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (17a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (17b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C X¹⁵—X¹⁶—  (17c)

wherein,

-   -   X¹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X² can be selected from an amino acid comprising a basic side        chain;    -   X³ can be C;    -   X⁴ can be selected from an amino acid comprising a basic side        chain;    -   X⁵ can be selected from an amino acid comprising a basic side        chain or an aromatic side chain or a large hydrophobic side        chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be P;    -   X⁹ can be G;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid;    -   X¹³ can be selected from an amino acid;    -   X¹⁴ can be C;    -   X¹⁵ can be selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ can be selected from an amino acid comprising a small        hydrophobic side chain.

In IL-2Rα ligands of Formula (17a)-(17c),

X¹ can be selected from F, I, L, M, V, W, and Y;

X² can be selected from H, K, and R;

X³ can be C;

X⁴ can be selected from H, K, and R;

X⁵ can be selected from F, H, I, K, L, M, R, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁴ can be C;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹ can be V.

In IL-2Rα ligands of Formula (17a)-(17c), X² can be selected from K, R,T, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X³ can be C.

In IL-2Rα ligands of Formula (17a)-(17c), X⁴ can be selected from K, F,R, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X⁵ can be selected from L, M,V, and R.

In IL-2Rα ligands of Formula (17a)-(17c), X⁶ can be selected from V, S,A, L, and E.

In IL-2Rα ligands of Formula (17a)-(17c), X⁷ can be selected from M, E,R, Y, V, and K.

In IL-2Rα ligands of Formula (17a)-(17c), X⁸ can be P.

In IL-2Rα ligands of Formula (17a)-(17c), X⁹ can be G.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁰ can be selected from S, R,L, Q, V, and G.

In IL-2Rα ligands of Formula (17a)-(17c), X¹¹ can be selected from G, V,T, M, and E.

In IL-2Rα ligands of Formula (17a)-(17c), X¹² can be selected from W, S,W, A, and M.

In IL-2Rα ligands of Formula (17a)-(17c), X¹³ can be selected from A, Y,E, V, and H.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁴ can be selected from H, T,L, V, F, and R.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁴ can be selected from F, A,and S.

In IL-2Rα ligands of Formula (17a)-(17c), X¹ can be V.

In IL-2Rα ligands of Formula (17a)-(17c), X² can be R.

In IL-2Rα ligands of Formula (17a)-(17c), X³ can be C.

In IL-2Rα ligands of Formula (17a)-(17c), X⁴ can be R.

In IL-2Rα ligands of Formula (17a)-(17c), X⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X⁵ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X⁵ can be selected from H, K,and R.

In IL-2Rα ligands of Formula (17a)-(17c), X⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X⁷ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X⁸ can be P.

In IL-2Rα ligands of Formula (17a)-(17c), X⁹ can be G.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹³ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (17a)-(17c), X¹⁶ can be S.

In IL-2Rα ligands of Formula (17a)-(17c), X¹ can be V, X², can be R, X³can be C, X⁴ can be R, X¹⁴ can be C, and X¹⁶ can be S.

In IL-2Rα ligands of Formula (17a)-(17c),

X¹ can be V;

X² can be R;

X³ can be C;

X⁴ can be R;

X⁵ can be selected from H, F, I, K, L, M, R, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹⁴ can be C;

X¹⁵ can be selected from F, I, L, M, V, W, and Y; and

X¹⁶ can be S.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 208 to SEQ ID NO: 213:

SEQ ID NO: 208 V K C K L V N P G S G W A C H F SEQ ID NO: 209 V R C F MS E P G R V S Y C T A SEQ ID NO: 210 V R C R L A R P G L T W E C L SSEQ ID NO: 211 V R C R V L Y P G Q M A V C V S SEQ ID NO: 212 V T C Y RA V P G V E A Y C F S SEQ ID NO: 213 V Y C R R E K P G G E M H C R S

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 205 to SEQ ID NO:213.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 205 to SEQ IDNO: 213, or a truncated amino acid sequence of any one of SEQ ID NO: 205to SEQ ID NO: 213, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 205 to SEQ IDNO: 213, or a truncated amino acid sequence of any one of SEQ ID NO: 205to SEQ ID NO: 213, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (18a) (SEQ ID NO: 214), the amino acid sequenceof Formula (18b) (SEQ ID NO: 215), or the amino acid sequence of Formula(18c) (SEQ ID NO: 216):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (18a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (18b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—X¹⁶—  (18c)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be selected from an amino acid;    -   X³ can be C;    -   X⁴ can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be P;    -   X⁹ can be G;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid;    -   X¹³ can be selected from an amino acid comprising an aromatic        side chain or a large hydrophobic side chain;    -   X¹⁴ can be C;    -   X¹⁵ can be selected from an amino acid; and    -   X¹⁶ can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rα ligands of Formula (18a)-(18c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from F, H, I, L, M, V, W, and Y;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be selected from F, H, I, L, M, V, W, and Y;

X¹⁴ can be C;

X¹⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹ can be selected from A, H,Q, R, T, and V.

In IL-2Rα ligands of Formula (18a)-(18c), X² can be selected from T, G,L, D, and K.

In IL-2Rα ligands of Formula (18a)-(18c), X³ can be C.

In IL-2Rα ligands of Formula (18a)-(18c), X⁴ can be selected from H, T,P, A, F, Q, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁵ can be selected from L, W,G, I, E, M, and R.

In IL-2Rα ligands of Formula (18a)-(18c), X⁶ can be selected from L, T,S, M, and N.

In IL-2Rα ligands of Formula (18a)-(18c), X⁷ can be selected from A, K,D, E, W, T, and S.

In IL-2Rα ligands of Formula (18a)-(18c), X⁸ can be P.

In IL-2Rα ligands of Formula (18a)-(18c), X⁹ can be G.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁰ can be selected from V, A,S, T, D, Q, and V.

In IL-2Rα ligands of Formula (18a)-(18c), X¹¹ can be selected from D, E,W, S, R, and I.

In IL-2Rα ligands of Formula (18a)-(18c), X¹² can be selected from N, W,G, V, P, and A.

In IL-2Rα ligands of Formula (18a)-(18c), X¹³ can be selected from T, V,P, F, Y, and W.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁴ can be selected from I, S,P, D, H, T, and V.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁴ can be selected from F, L,N, I, T, and G.

In IL-2Rα ligands of Formula (18a)-(18c), X¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X³ can be C.

In IL-2Rα ligands of Formula (18a)-(18c), X⁴ can be selected from F, H,I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁴ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁵ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁷ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X⁸ can be P.

In IL-2Rα ligands of Formula (18a)-(18c), X⁹ can be G.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁰ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹² can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹³ can be selected from F, H,I, L, M, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹³ can be selected from F, W,and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁴ can be C.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁵ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X¹⁶ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (18a)-(18c), X³ can be C, X⁸ can be P, X⁹can be G, and X¹⁴ can be C.

In IL-2Rα ligands of Formula (18a)-(18c),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X³ can be C;

X⁴ can be selected from F, H, W, and Y;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be P;

X⁹ can be G;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be selected from F, H, W, and Y;

X¹⁴ can be C;

X¹⁵ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y; and

X¹⁶ can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 217 to SEQ ID NO: 224:

SEQ ID NO: 217 A T C H L L A P G V D N T C I F SEQ ID NO: 218 H G C T LT K P G A E W V C S F SEQ ID NO: 219 Q L C P W S D P G S W G P C P LSEQ ID NO: 220 R D C A G M E P G T S V F C D N SEQ ID NO: 221 R D C F IL E P G T S V Y C D L SEQ ID NO: 222 T D C Q E T W P G D R P W C H ISEQ ID NO: 223 V K C F M S T P G Q I A Y C T T SEQ ID NO: 224 V K C Y RN S P G V E A Y C V G

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 214 to SEQ ID NO:224.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 214 to SEQ IDNO: 224, or a truncated amino acid sequence of any one of SEQ ID NO: 214to SEQ ID NO: 224, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 214 to SEQ IDNO: 224, or a truncated amino acid sequence of any one of SEQ ID NO: 214to SEQ ID NO: 224, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (19a) (SEQ ID NO: 225), or the amino acidsequence of Formula (19b) (SEQ ID NO: 226):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (19a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (19b)

wherein,

-   -   X¹ can be selected from an amino acid;    -   X² can be C;    -   X³ can be selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X⁴ can be selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X⁵ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X⁶ can be selected from an amino acid comprising a polar/neutral        side chain;    -   X⁷ can be selected from an amino acid;    -   X⁸ can be selected from an amino acid;    -   X⁹ can be selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹⁰ can be selected from an amino acid;    -   X¹¹ can be selected from an amino acid;    -   X¹² can be selected from an amino acid;    -   X¹³ can be C; and    -   X¹⁴ can be selected from an amino acid.

In IL-2Rα ligands of Formula (19a)-(19b),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be C;

X³ can be selected from D, E, N, Q, S, T, and Y;

X⁴ can be selected from D, E, N, Q, S, T, and Y;

X⁵ can be selected from F, I, L, M, V, W, and Y;

X⁶ can be selected from N, Q, S, T, and Y;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from F, I, L, M, V, W, and Y;

X¹⁰ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X¹³ can be C; and

X¹⁴ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹ can be selected from D, P,S, T, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X² can be C.

In IL-2Rα ligands of Formula (19a)-(19b), X³ can be selected from L, Q,M, E, W, and H.

In IL-2Rα ligands of Formula (19a)-(19b), X⁴ can be selected from D, R,S, E, and L.

In IL-2Rα ligands of Formula (19a)-(19b), X⁵ can be selected from L, P,F, and V.

In IL-2Rα ligands of Formula (19a)-(19b), X⁶ can be selected from R, A,K, H, and W.

In IL-2Rα ligands of Formula (19a)-(19b), X⁷ can be selected from G, E,K, R, D, G, and Q.

In IL-2Rα ligands of Formula (19a)-(19b), X⁸ can be selected from T, Y,S, M, Q, and D.

In IL-2Rα ligands of Formula (19a)-(19b), X⁹ can be selected from V, Y,and D.

In IL-2Rα ligands of Formula (19a)-(19b), X¹⁰ can be selected from G, S,E, N, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹¹ can be selected from M, Q,W, V, E, N, R, L, and M.

In IL-2Rα ligands of Formula (19a)-(19b), X¹² can be selected from V, Q,W, V, E, N, R, L, and M.

In IL-2Rα ligands of Formula (19a)-(19b), X¹³ can be C.

In IL-2Rα ligands of Formula (19a)-(19b), X¹⁴ can be selected from Q, L,D, N, I, P, and F.

In IL-2Rα ligands of Formula (19a)-(19b), X¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X² can be C.

In IL-2Rα ligands of Formula (19a)-(19b), X³ can be selected from H, N,Q, S, T, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X³ can be selected from D andE.

In IL-2Rα ligands of Formula (19a)-(19b), X³ can be selected from Q andE.

In IL-2Rα ligands of Formula (19a)-(19b), X⁴ can be selected from D andE.

In IL-2Rα ligands of Formula (19a)-(19b), X⁵ can be L.

In IL-2Rα ligands of Formula (19a)-(19b), X⁶ can be selected from R, H,and K.

In IL-2Rα ligands of Formula (19a)-(19b), X⁷ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X⁸ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X⁹ can be Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹⁰ can be selected from A, G,P, S, and T.

In IL-2Rα ligands of Formula (19a)-(19b), X¹¹ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹² can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹² can be selected from V, L,and M.

In IL-2Rα ligands of Formula (19a)-(19b), X¹³ can be C.

In IL-2Rα ligands of Formula (19a)-(19b), X¹⁴ can be selected from F, I,L, M, V, W, and Y.

In IL-2Rα ligands of Formula (19a)-(19b), X¹⁴ can be selected from F, I,and L.

In IL-2Rα ligands of Formula (19a)-(19b), X² can be C, X⁵ can be L, andX¹³ can be C.

In IL-2Rα ligands of Formula (19a)-(19b),

X¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X² can be C;

X³ can be selected from D, E, N, Q, S, T, and Y;

X⁴ can be selected from D, E, N, Q, S, T, and Y;

X⁵ can be L;

X⁶ can be selected from A, G, H, K, P, S, and T;

X⁷ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁸ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y;

X⁹ can be selected from F, I, L, M, V, W, and Y;

X¹⁰ can be selected from A, G, P, S, and T;

X¹¹ can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,V, W, and Y; and

X¹² can be selected from F, I, L, M, V, W, and Y;

X¹³ can be C; and

X¹⁴ can be selected from F, I, L, M, V, W, and Y.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 227 to SEQ ID NO: 234:

SEQ ID NO: 227 D C L D L R G T V G M V C Q SEQ ID NO: 228 P C Q R L A EY Y S Q Q C L SEQ ID NO: 229 S C M D L K G S V G W V C D SEQ ID NO: 230T C E S L A K M Y E V E C N SEQ ID NO: 231 T C E S L A R M Y N E N C ISEQ ID NO: 232 W C W E P H D Q Y Y V R C P SEQ ID NO: 233 Y C H D F K GT V G T L C I SEQ ID NO: 234 G C Q L V W Q D D S Y M C F Y

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 225 to SEQ ID NO:234.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 225 to SEQ IDNO: 234, or a truncated amino acid sequence of any one of SEQ ID NO: 225to SEQ ID NO: 234, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 225 to SEQ IDNO: 234, or a truncated amino acid sequence of any one of SEQ ID NO: 225to SEQ ID NO: 234, wherein the amino acid sequence comprises one or moreamino acid substitution such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise the aminoacid sequence of Formula (20a) (SEQ ID NO: 235), or the amino acidsequence of Formula (20b) (SEQ ID NO: 236):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (20a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (20b)

wherein,

-   -   X¹ can be W;    -   X² can be C;    -   X³ can be selected from F, I, L, M, V, W, and Y;    -   X⁴ can be G;    -   X⁵ can be Q;    -   X⁶ can be P;    -   X⁷ can be L;    -   X⁸ can be selected from F, I, L, M, V, W, and Y;    -   X⁹ can be R;    -   X¹⁰ can be selected from H, N, Q, F, I, L, M, V, W, and Y;    -   X¹¹ can be G;    -   X¹² can be S;    -   X¹³ can be C; and    -   X¹⁴ can be K.

In IL-2Rα ligands of Formula (20a)-(20b), X³ can be selected from I andV.

In IL-2Rα ligands of Formula (20a)-(20b), X⁸ can be selected from F andY.

In IL-2Rα ligands of Formula (20a)-(20b), X¹⁰ can be selected from F, I,L, M, N, Q, S, T, V, W, and Y.

In IL-2Rα ligands of Formula (20a)-(20b), X¹⁰ can be selected from L andQ.

In IL-2Rα ligands of Formula (20a)-(20b), X¹ can be W, X² can be C, X⁴can be G, X⁵ can be Q, X⁶ can be P, X⁷ can be L, X⁹ can be R, X¹¹ can beG, X¹² can be S, X¹¹ can be C, and X¹⁴ can be K.

In IL-2Rα ligands of Formula (20a)-(20b),

X¹ can be W;

X² can be C;

X³ can be selected from I and V;

X⁴ can be G;

X⁵ can be Q;

X⁶ can be P;

X⁷ can be L;

X⁸ can be selected from F and Y;

X⁹ can be R;

X¹⁰ can be selected from F, H, I, L, M, N, Q, S, T, V, W, and Y;

X¹¹ can be G;

X¹² can be S;

X¹³ can be C; and

X¹⁴ can be K.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from an one of SE ID NO: 237 to SE ID NO: 307:

SEQ ID NO: 237 W C I G Q P L F R Q G S C K SEQ ID NO: 238 W C V G Q P LY R L G S C K SEQ ID NO: 239 W D Q F Q L G W E A G V A A SEQ ID NO: 240F L P W P V Y F S Q V L G G G SEQ ID NO: 241 Y V M C S A F G C K S ISEQ ID NO: 242 H V I C S V N G G C R G SEQ ID NO: 243 I R F C L R S E PT A C W I V SEQ ID NO: 244 I R C R Y E K Q S G I C L F SEQ ID NO: 245 GG C S L V W A D S W V C I F SEQ ID NO: 246 G C S L M W Q D G W W V C ISEQ ID NO: 247 E W E C R F L P G R R G C S L F SEQ ID NO: 248 K G C T LQ N P G S G W V C L F SEQ ID NO: 249 T C R L K R S G P N S W E C ISEQ ID NO: 250 W C I G Q P L F R Q G S C K SEQ ID NO: 251 A V S C N S WR C I P W SEQ ID NO: 252 A V C C D G N S C R R C SEQ ID NO: 253 F V H CS L M G C W C G SEQ ID NO: 254 R C L D L G G S V G L V C FSEQ ID NO: 255 V C F N F R G T V G R H C W SEQ ID NO: 256 V R C R Q N EP G G A Y W C S S SEQ ID NO: 257 C V L R E G A E G W E C V W RSEQ ID NO: 258 C R M M Q G T Y G W T C L F SEQ ID NO: 259 C I L N D T IQ G W V C I Y SEQ ID NO: 260 C T L Y R S A P G V W L C I FSEQ ID NO: 261 C L V F D Q Y G N Y K R R C SEQ ID NO: 262 I V C C N M FG C H T C R N SEQ ID NO: 263 Q V C C T S R G C R V C A P VSEQ ID NO: 264 R V C C S M V G C R S C N L SEQ ID NO: 265 R V C C T F AG C R V C H K SEQ ID NO: 266 R V C C T S D G C R G C R Q SEQ ID NO: 267T V C C T V Q G C W P C S R SEQ ID NO: 268 V C C H Q T F G C Y R C K QSEQ ID NO: 269 C V V C S A L G C R A C V P R SEQ ID NO: 270 V W D C F VR G W E A G V A A V G E SEQ ID NO: 271 L T C L I F K P G T H R H C P VSEQ ID NO: 272 R Y C S P L I P G S A L G C P R SEQ ID NO: 273 I R C R LD P P G S Y K T C V F SEQ ID NO: 274 R G V I C N H A G C R I W Y GSEQ ID NO: 275 T T Q S C T L R Y C W L L Q SEQ ID NO: 276 W W I S C L RD L R C L E Y F SEQ ID NO: 277 R H A C K T W Y R M C I V SSEQ ID NO: 278 A V S C S R L T G R C H S L SEQ ID NO: 279 W V A C N R VT G S C R P I SEQ ID NO: 280 S H G V C C T Q S S C R S C RSEQ ID NO: 281 W V A C N R L S G C C R P I SEQ ID NO: 282 H T V C C Q DW G C R S C S G SEQ ID NO: 283 M A C C T P R G C R P C SEQ ID NO: 284 RS V C C S S Y G C R A C F G SEQ ID NO: 285 C K L T C T S S T C S C V FSEQ ID NO: 286 C M L K C T N A I C E C I F SEQ ID NO: 287 C R V W C N QA E C M C I F SEQ ID NO: 288 S R C S F D V T K Q E C V F SEQ ID NO: 289L E C Q P Y R G P L Y Y C Q D SEQ ID NO: 290 S I C C T P Q L C H S C D GSEQ ID NO: 291 T T C C T S E G C H K C I T L SEQ ID NO: 292 C V A C S SD G C S P I I C SEQ ID NO: 293 A I C S E D E G G E L C C W HSEQ ID NO: 294 H E I C C G P P G C H S C S V T SEQ ID NO: 295 L S V C SC P P G Q L Y C M V E SEQ ID NO: 296 S T W C C L H P G V G E C Q A VSEQ ID NO: 297 V T Q C F D G P G S F R C C Y Q SEQ ID NO: 298 R Q C N CL S P G E L V N C Q Q SEQ ID NO: 299 M V S C T D L G C V V V G G GSEQ ID NO: 300 V V H C L Q S G C Y S V G S G SEQ ID NO: 301 T I K C G SS G W C W V E A G SEQ ID NO: 302 M V S C T D L G C V V V G G GSEQ ID NO: 303 H E I C C G P P G C H S C S V T SEQ ID NO: 304 L S V C SC P P G Q L Y C M V E SEQ ID NO: 305 S T W C C L H P G V G E C Q A VSEQ ID NO: 306 V T Q C F D G P G S F R C C Y Q SEQ ID NO: 307 R Q C N CL S P G E L V N C Q Q

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 235 to SEQ ID NO:307.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 235 to SEQ IDNO: 307, or a truncated amino acid sequence of any one of SEQ ID NO: 235to SEQ ID NO: 307, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 235 to SEQ IDNO: 307, or a truncated amino acid sequence of any one of SEQ ID NO: 235to SEQ ID NO: 307, wherein the amino acid sequence comprises one or moreamino acid substitution such as from 1 to 5 amino acid substitutions.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from any one of SEQ ID NO: 400 to SEQ ID NO: 423:

SEQ ID NO: 400 W D D F I L G W E A G V A A V G E V SEQ ID NO: 401 F L PW P V Y F S Q V L G G R R SEQ ID NO: 402 Y V M C S A F G C K S I G GSEQ ID NO: 403 H V I C S V N G G C R G G G SEQ ID NO: 404 G G I R F C LR S E P T A C W I V G G SEQ ID NO: 405 G G I R C R Y E K Q S G I C L F GG SEQ ID NO: 423 G G G G C S L V W A D S W V C I F G G SEQ ID NO: 406 GG G C S L M W Q D G W W V C I G G SEQ ID NO: 407 G G E W E C R F L P G RR G C S L F G G SEQ ID NO: 408 G G K G C T L Q N P G S G W V C L F G GSEQ ID NO: 409 G G T C R L K R S G P N S W E C I G G SEQ ID NO: 410 G GW C I G Q P L F R Q G S C K G G SEQ ID NO: 411 F V L C G L Q G C R S G GSEQ ID NO: 412 F V P W D E Y F L Q I L G G SEQ ID NO: 413 G G G W V I CS A L G C P F G G SEQ ID NO: 414 G G G R R F C L R S E P T A C W T V G GSEQ ID NO: 415 G G G S R C S L V W A D S W V C I F G G SEQ ID NO: 416 GG D W E C L F L P G R R G C T L F G G SEQ ID NO: 417 F I P W D E Y F A QL L G G SEQ ID NO: 418 F V P W D V Y F S Q I L G G SEQ ID NO: 419 F I PW D E Y F K Q V L G G SEQ ID NO: 420 F V P W P E Y F L Q I M G GSEQ ID NO: 421 F I P W E E Y F S Q L L G G SEQ ID NO: 422 F I P W P E YF S Q L L G G

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 400 to SEQ ID NO:423.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 400 to SEQ IDNO: 423, or a truncated amino acid sequence of any one of SEQ ID NO: 400to SEQ ID NO: 423, wherein the amino acid sequence can independentlycomprise from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus,on the C-terminus, or on both the N- and C-termini.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 400 to SEQ IDNO: 423, or a truncated amino acid sequence of any one of SEQ ID NO: 400to SEQ ID NO: 423, wherein the amino acid sequence comprises one or moreamino acid substitutions such as from 1 to 5 amino acid substitutions.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 1 to SEQ ID NO:307 and SEQ ID NO. 400 to SEQ ID NO: 423.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence having greater than 70%, greater than 75%, greaterthan 80%, greater than 85%, greater than 90%, or greater than 95%sequence similarity to any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQID NO. 400 to SEQ ID NO: 423.

An IL-2Rα ligand provided by the present disclosure can comprise atruncated amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO:307 and SEQ ID NO. 400 to SEQ ID NO: 423.

An IL-2Rα ligand provided by the present disclosure can comprise anamino acid sequence having greater than 70%, greater than 75%, greaterthan 80%, greater than 85%, greater than 90%, or greater than 95%sequence similarity to a truncated amino acid sequence of any one of SEQID NO: 1 to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.

IL-2Rα ligands provided by the present disclosure can comprise an aminoacid sequence selected from SEQ ID NO: 1 to SEQ ID NO: 307 independentlycomprising one or more such as from 1 to 5 or from 1 to 3 of thefollowing conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S) and threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S) or threonine (T); amino acids having anacidic side chain comprising aspartate (D) and glutamate (E); aminoacids having a polar neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), and tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W).

Small peptidyl IL-2Rα ligands provided by the present disclosure caninclude naturally amino acids or can be modified to include non-naturalamino acids. Because the small peptidyl IL-2Rα ligands can be chemicallysynthesized, the peptidyl IL-2Rα ligands can be modified using naturaland/or non-natural amino acids to optimize potency and efficacy, and toimprove metabolic stability. The small peptidyl IL-2Rα ligands alsoallow such modifications to be made with a low likelihood of inducingimmunogenicity. Also, due to their chemical malleability, peptides canbe caged to construct a reversibly inactive prodrug using cell-specificenvironmental triggers such as proteases, or complexes sensitive to lowpH. For example, the pH-dependent binding properties of peptides can beoptimized by use of non-natural amino acids having sidechain ionizablegroups with a pKa in the range of pH 5.0 to pH 8.0. As with proteins,pharmacokinetic-enhancing moieties, such as polyethylene glycol (PEG),can be appended to peptides, either as part of, or independent of, a“caging” strategy. Also, sites on a peptide can be reserved forattaching a variety of cell targeting moieties, such as tumor-specificantibodies and immune cell-specific targeting moieties. These featuresof peptidyl IL-2Rα ligands can be exploited in the design of optimaltherapeutic candidates based on the peptidyl IL-2Rα ligands provided bythe present disclosure.

In addition to peptides consisting only of naturally occurring aminoacids, peptidomimetics or peptide analogs are also provided. Peptidemimetics can be used to produce an equivalent or enhanced therapeuticeffect. Peptidomimetics are structurally similar to a paradigm peptide,for example, an IL-2Rα ligand that has a biological or pharmacologicalactivity, but have one or more peptide linkages optionally replaced by alinkage such as —CH₂—NH—, —CH₂—S—, —CH₂—CH₂—, —CH═CH— (cis and trans),—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods known in the art.

Substitution of one or more amino acids of a consensus sequence with aD-amino acid of the same type, such as D-lysine in place of L-lysine,may be used to generate more stable peptides. In addition, constrainedpeptides comprising a consensus sequence, or a substantially identicalconsensus sequence variation may be generated by methods known in theart; for example, by adding internal cysteine residues capable offorming intramolecular disulfide bridges which cyclize the peptide.

One or more amino acids of an IL-2Rα ligand consensus sequence may bereplaced with a synthetic or non-naturally occurring amino acid.Synthetic or non-naturally occurring amino acids refer to amino acidswhich do not naturally occur in vivo but which, nevertheless, can beincorporated into the peptidyl ligands provided by the presentdisclosure. Suitable examples of synthetic amino acids include theD-α-amino acids of naturally occurring L-α-amino acid as well asnon-naturally occurring D- and L-α-amino acids represented by theformula H₂NCHRCOOH where R can be C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl; an aromatic residue of from 6 to 10 carbon atomsoptionally having from 1 to 3 substituents on the aromatic nucleusselected from the group consisting of hydroxyl, lower alkoxy, amino, andcarboxyl; -alkylene-Y where alkylene is an alkylene group of from 1 to 7carbon atoms and Y is selected from a hydroxyl, amino, cycloalkyl, andcycloalkenyl having from 3 to 7 carbon atoms; C₆₋₁₀ aryl, such as from 1to 3 substituents on the aromatic nucleus selected from the groupconsisting of hydroxyl, lower alkoxy, amino and carboxyl; heterocyclicof from 3 to 7 carbon atoms and 1 to 2 heteroatoms selected from thegroup consisting of oxygen, sulfur, and nitrogen; —C(O)R where R isselected from hydrogen, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, and —NR₂ whereeach R is independently selected from hydrogen and C₁₋₄ alkyl;—S(O)_(n)R where n is 1 or 2 and R is C₁₋₆ alkyl and with the provisothat R does not define a side chain of a naturally occurring amino acid.Examples of synthetic amino acids include amino acids wherein the aminogroup is separated from the carboxyl group by more than one carbon atomsuch as b-alanine and g-aminobutyric acid. Other examples of suitablesynthetic amino acids include the D-amino acids of naturally occurringL-amino acids, L-1-naphthyl-alanine, L-2-naphthylalanine,L-cyclohexylalanine, L-2-amino isobutyric acid, the sulfoxide andsulfone derivatives of methionine (i.e., HOOC—(H₂NCH)CH₂CH₂—S(O)_(n)R⁶)where n and R₆ are as defined above as well as the lower alkoxyderivative of methionine (i.e., HOOC— (H₂NCH)CH₂CH₂OR where R is C₁₋₆alkyl and where R does not define a side chain of a naturally occurringamino acid).

IL-2Rα ligands include bioisosteres and isosteres of the IL-2Rα ligandsprovided by the present disclosure.

An IL-2Rα ligand provided by the present disclosure can have, forexample, less than 20 amino acids, less than 15 amino acids, or lessthan 10 amino acids. For example, an IL-2Rα ligand can have from 5 to 20amino acids, or from 10 to 15 amino acids.

IL-2Rα ligands of SEQ ID NO: 1 to SEQ ID NO: 307 exhibit an affinity(IC₅₀) to the human IL-2Rα subunit of less than 100 μM.

An IL-2Rα ligand provided by the present disclosure can comprise, forexample, from 5 to 50 amino acids, from 5 to 40 amino acids, from 5 to35 amino acids, from 5 to 30 amino acids, from 6 to 25 amino acids, orfrom 7 to 20 amino acids.

An IL-2Rα ligand provided by the present disclosure can bind to thehuman IL-2Rα subunit, to a mammalian IL-2Rα subunit, or to both thehuman IL-2Rα subunit and a mammalian IL-2Rα subunit with an IC₅₀, forexample, from 1 μM to 100 μM, from 10 μM to 10 μM, from 100 μM to 1 μM,from, 0.001 μM to 1 μM, or from 0.01 μM to 1 μM.

An IL-2Rα ligand provided by the present disclosure can bind to, forexample, the human IL-2Rα subunit with an IC₅₀ from 0.1 μM to 50 μM.

An IL-2Rα ligand provided by the present disclosure can bind to thehuman IL-2Rβ subunit and/or human IL-2Rγc subunit with an IC₅₀, forexample, of greater than 100 μM, greater than 1 mM, greater than 10 mM,or greater than 100 nM.

IL-2Rα ligands and the sub-genuses of IL-2Rα ligands provided by thepresent disclosure do not include an IL-2Rα ligand having an amino acidsequence selected from SEQ ID NO: 308 to SEQ ID NO: 397.

SEQ ID NO: 308 F V R C S A N G C V SEQ ID NO: 309 S V R C S A S G C VSEQ ID NO: 310 Y V A C S V S G C V SEQ ID NO: 311 Y V I C G A S G C VSEQ ID NO: 312 Y V R C T A I G C V SEQ ID NO: 313 F V R C S A T G C VSEQ ID NO: 314 Y V I C S A S G C V SEQ ID NO: 315 W V R C S A S G C VSEQ ID NO: 316 F V R C S A S G C V SEQ ID NO: 317 F V R C T A S G C VSEQ ID NO: 318 F V R C T S D G C V SEQ ID NO: 319 Y V R C T A S G C VSEQ ID NO: 320 F R R C S A S G C V SEQ ID NO: 321 L R R C S A N G C VSEQ ID NO: 322 L R R C S A N G C V SEQ ID NO: 323 F V R C S L I G C VSEQ ID NO: 324 F V R C N A S G C V SEQ ID NO: 325 F V R C T R E G C VSEQ ID NO: 326 F V R C T S D G C V SEQ ID NO: 327 Y V I C S A S G C VSEQ ID NO: 328 F V R C T E W G C V SEQ ID NO: 329 F V R C T A S G C ISEQ ID NO: 330 Y V R C S E S G C V G S S W N A SEQ ID NO: 331 F V R C SE S G C V G S S W S A SEQ ID NO: 332 Y V R C S A S G C V G S S W F LSEQ ID NO: 333 Y V R C S D S G C V G S T W G W SEQ ID NO: 334 Y V R C SE S G C V G S T W V F SEQ ID NO: 335 Y V R C S E S G C V G S T W V FSEQ ID NO: 336 Y V L C A L S G C V G S S W S S SEQ ID NO: 337 Y V R C GE S G C V G S T W S T SEQ ID NO: 338 Y V R C S A T G C V G S T W T FSEQ ID NO: 339 Y V R C G E T G C V G S T W S F SEQ ID NO: 340 Y V R C GV S G C V G S S W V L SEQ ID NO: 341 Y V R C G E S G C V G S T W S TSEQ ID NO: 342 F V R C S E S G C V G S S W S T SEQ ID NO: 343 Y V R C SE S G C V G S S W W A SEQ ID NO: 344 Y V R C S V T G C V G S S W S ISEQ ID NO: 345 Y V R C S V T G C V G S S W S I SEQ ID NO: 346 Y V R C SE S G C V G S S W S V SEQ ID NO: 347 F V R C S A D G C V G S S W L QSEQ ID NO: 348 Y V R C S A D G C V G S S W I T SEQ ID NO: 349 Y V R C NP S G C V G S S W S I SEQ ID NO: 350 Y V R C S V T G C V G S S W S ISEQ ID NO: 351 Y V R C S E S G C V G S S W S V SEQ ID NO: 352 F V R C SA N G C V G S T W Q A SEQ ID NO: 353 Y V R C T E S G C V G S T W T YSEQ ID NO: 354 Y V R C S V T G C V G S T W S V SEQ ID NO: 355 Y V R C SE I G C V G S T W S L SEQ ID NO: 356 T V R C S A T G C V G S S W V GSEQ ID NO: 357 Y V R C S A T G C V G S S W V G SEQ ID NO: 358 F V R C SA S G C V G S S W V G SEQ ID NO: 359 Y V R C S A D G C V G S T W N LSEQ ID NO: 360 Y V R S S Q S G C V G S G W V L SEQ ID NO: 361 Y V A C SE S G C V G S S W S V SEQ ID NO: 362 F V A C G E L G C V G S S W S ISEQ ID NO: 363 Y V A C S E S G C V G S S W L A SEQ ID NO: 364 Y C R C TE S G C V G S T W T Y SEQ ID NO: 365 F V R C T A I G C V G S S W S VSEQ ID NO: 366 Y V R C S A D G C V G S S W S A SEQ ID NO: 367 Y V R C SA S G C V G S S W N Y SEQ ID NO: 368 Y V L C S A S G C V G S L W T HSEQ ID NO: 369 Y V R C T D S G C V G S S W H L SEQ ID NO: 370 Y V A C SE S G C V G S T W I T SEQ ID NO: 371 Y V A C S E S G C V G S T W T FSEQ ID NO: 372 Y V R C G A A G C V V S S W V Y SEQ ID NO: 373 F V R C GA S G C V G S T W G S SEQ ID NO: 374 Y V A C S E I G C V G S T W S LSEQ ID NO: 375 Y V A C S E S G C V G S S W T W SEQ ID NO: 376 Y V A C SV S G C V G S S W S V SEQ ID NO: 377 Y V R C S E S G C V G S T W T TSEQ ID NO: 378 Y V R C S E S G C V S S F W S A P W K A SEQ ID NO: 379 YV R C S E N G C V G H S W T Q G L R T SEQ ID NO: 380 Y V R C S E S G C VS Q R P H V L E V W SEQ ID NO: 381 Y V L C S E R G C V G Q N W A V G K LP SEQ ID NO: 382 Y V R C S E I G C V G S H W S S Y G K H SEQ ID NO: 383Y V R C S E N G C V G S S W G R V T L D SEQ ID NO: 384 Y V R C S E S G CV G C E L V W Y F I T SEQ ID NO: 385 Y V R C S E S G C V G S S W G A V AS I SEQ ID NO: 386 Y V R C S E S G C V G S S W G A V A S ISEQ ID NO: 387 Y V R C S E S G C V G S S W S V S P R G SEQ ID NO: 388 YV R C G E S G C V S S S W S T M G N S SEQ ID NO: 389 Y V R C S E N G C VG S S W E H S A I I SEQ ID NO: 390 Y V R C S E G G C V G S T W T A S Y PN SEQ ID NO: 391 Y V R C S E S G C V G S T W N G V L S R SEQ ID NO: 392Y V R C S E S G C V G S T W N G V L S R SEQ ID NO: 393 T V R C S Q S G CV G C Q L V W Y F T T SEQ ID NO: 394 Y V N C S Q S G C V G S T W N G V FS N SEQ ID NO: 395 Y V A C S E S G C V S V D S S A G A L FSEQ ID NO: 396 Y V R C N E T G C V G S S W I A A G P F SEQ ID NO: 397 YV R C S E S G C V G S T W L F N P W G

Compounds provided by the present disclosure comprise at least oneIL-2Rα ligand. Compounds can comprise, for example, from 1 to 10 IL-2Rαligands, from 1 to 6 IL-2Rα ligand, or from 1 to 3 IL-2Rα ligands.Examples of compounds comprising at least one IL-2Rα ligand includepeptides and conjugates. Examples of conjugates include one or moreIL-2Rα ligands bound to a polypeptide, a macromolecule such as apolyethylene glycol, a fusion protein, or a biological molecule such asan antibody.

Functionally, compounds comprising at least one IL-2Rα ligand can beIL-2Rαβγc agonists, IL-2Rα antagonists, IL-2Rαβ antagonists, IL-2Rαβγcantagonists, IL-2Rαβγc antagonists, diagnostic reagents, imagingreagents, targeting compounds, cytotoxic compounds, and compoundsexhibiting dual pharmacology.

Compounds comprising an IL-2Rα ligand provided by the present disclosurecan have a molecular weight, for example, from 1,000 to 400,000 Da, from1,000 to 200,000 Da, from 1,000 to 100,000 Da, from 1,000 Da to 20,000Da, from 1,500 Da to 15,000 Da, from 2,000 Da to 10,000 Da, or from5,000 Da to 10,000 Da.

Compounds comprising an IL-2Rα provided by the present disclosure can beattached to one or more moieties that impart a property to the compoundthat enhances therapeutic efficacy. Examples of properties includepotency, aqueous solubility, polarity, lipophilicity, pharmacokinetics,targeting, bioavailability, pH-dependent binding, bioactivity,pharmacodynamics, cellular activity, metabolism, efficacy, reversibleincapacitation (caging), selectivity, or a combination of any of theforegoing.

Compounds comprising an IL-2Rα ligand can comprise one or more moietiesthat are cleavable in vivo. The moiety can be cleavable in a targetspecific environment such as, for example, by a target specific ortarget enriched enzyme, or pH. The moiety can be cleavable upon exposureto electromagnetic energy such as visible light or infrared radiationand/or by exposure to thermal energy.

Compounds comprising an IL-2Rα ligand can include a polymer, a peptide,an antibody.

Compounds comprising an IL-2Rα ligand can include a tumor-targetingmoiety such as, for example, a tumor-specific antibody, a tumor-specificantibody fragment, a tumor-specific protein, a tumor-specific peptide, anon-peptidyl tumor cell ligand, or a combination of any of theforegoing.

Compounds comprising an IL-2Rα ligand can comprise a caged molecule ormolecules. A caged molecule can in effect encapsulate the compound andcan serve to prevent bioactivity in certain tissues, for example, toprotect peripheral tissues from the toxicity of IL-2Rαβγc activation.

Compounds comprising an IL-2Rα ligand can comprise a moiety, wherein themoiety comprises a small molecule, a peptide, a polymer, or an antibody.The small molecule can be a non-peptidyl molecule. The moiety canexhibit a pharmacological effect. The pharmacological effect canmanifest when the moiety is bound to the IL-2Rα and/or after the moietyis cleaved from the compound comprising an IL-2Rα ligand.

Compounds comprising an IL-2Rα ligand can comprise a moiety configuredto sustain a circulating reservoir of the compound comprising an IL-2Rαligand.

Compounds comprising an IL-2Rα ligand can comprise a moiety configuredto target the IL-2R-directed immuno-stimulation of the effector immunecells in the tumor.

Compounds comprising an IL-2Rα ligand can comprise a moiety configuredto target specific immune cells such as Treg cells.

The moiety can comprise a compound that is toxic to a cell targeted bythe compound comprising an IL-2Rα ligand. A compound comprising anIL-2Rα ligand can target cells having a high expression level of theIL-2Rα subunit such as Treg cells and the compound can comprise a moietytoxic to the cells expressing the IL-2Rα subunit such as Treg cells. Thetoxic moiety can be cleavable or otherwise activated such as by exposureto electromagnetic radiation. The toxic moiety can be activated byexposure to electromagnetic radiation.

Compounds comprising an IL-2Rα ligand provided by the present disclosurecan activate the IL-2 receptor. Compounds comprising an IL-2Rα ligandprovided by the present disclosure can inhibit the IL-2 receptor.Certain compounds comprising an IL-2Rα ligand provided by the presentdisclosure can bind to the IL-2α subunit and prevent other compoundsfrom binding to the IL-2α subunit. Compounds comprising an IL-2Rα ligandcan reduce the potency of or interfere with the binding of IL-2Ragonists to cells that highly express the IL-2Rα ligand. Compoundscomprising an IL-2Rα ligand can reduce the sensitivity of Treg cells toIL-2.

Peptides provided by the present disclosure include at least one IL-2Rαligand. A peptide can include, for example, less than 50 amino acids,which include the amino acids constituting the IL-2Rα ligand.

A peptide comprising an IL-2Rα ligand can comprise, for example, from 5to 100 amino acids, from 5 to 80 amino acids, from 5 to 50 amino acids,from 10 to 40 amino acids, from 10 to 30 amino acids, or from 15 to 25amino acids.

In addition to an IL-2Rα ligand, a peptide can include additional aminoacids, for example, for establishing the conformation of an IL-2Rαligand and/or for coupling the IL-2Rα ligand to other compounds. Theadditional amino acids can be bonded to the N-terminus and/or to theC-terminus of the IL-2Rα ligand.

Conjugates provided by the present disclosure include at least oneIL-2Rα ligand.

A conjugate can comprise a polypeptide.

A polypeptide can be a single chain tandem peptide having two moreIL-2Rα ligands. The IL-2Rα ligands can be bonded through amino acidlinkers.

An amino acid linker can comprise, for example, more than one aminoacid, greater than 5 amino acids, greater than 10 amino acids, greaterthan 50 amino acids, or greater than 100 amino acids. A peptide linkercan comprise, for example, from 1 to 100 amino acids from 3 amino acidsto 75 amino acids, from 5 amino acids to 50 amino acids, or from 10amino acids to 25 amino acids.

For example, in a homodimer, the C-terminus of a first IL-2Rα ligand andthe C-terminus of a second IL-2Rα ligand can be attached to the linker;the N-terminus of a first IL-2Rα ligand and the N-terminus of a secondIL-2Rα ligand can be attached to the linker; or the C-terminus of afirst IL-2Rα ligand and the N-terminus of a second IL-2Rα ligand can beattached to the linker.

A polypeptide comprising an IL-2Rα ligand provided by the presentdisclosure can comprise, for example, from 5 amino acids to 4,000 aminoacids, from 5 amino acids to 3,000 amino acids, from 5 amino acids to2,500 amino acids, or from 5 amino acids to 2,000 amino acids.

A polypeptide can be a synthetic peptide or a recombinant polypeptide.

A single chain tandem peptide can be a heteromer having at least oneIL-2Rα ligand in combination with one or more IL-2Rβ ligands and/or oneor more IL-2Rγc ligands. For example, a single chain tandem peptide cancomprise an IL-2Rα ligand, an IL-2Rβ ligand, and an IL-2Rγc ligand withamino acid linkers coupling adjacent ligands. A single chain tandempeptide can further include additional amino acids at the N-terminusand/or C-terminus of the polypeptide.

The IL-2Rα and IL-2Rβ ligand and/or IL-2Rγc ligand can be arranged inany order.

Each of the adjacent ligands can independently be coupled through theN-terminus of each ligand, through the C-terminus of each ligand,through the N-terminus and C-terminus of the adjacent ligands, orthrough the side chains of the ligands and/or linkers.

For example, in a heteromer, the C-terminus of an IL-2Rα ligand can beattached to the linker and the N-terminus of an IL-2Rβ ligand or theN-terminus of an IL-2Rγc ligand can be attached to the linker; theC-terminus of an IL-2Rβ ligand or the N-terminus of an IL-2Rγc ligandcan be attached to the linker, or the N-terminus of an IL-2Rα ligand canbe attached to the linker. Other examples of suitable linkers includeDIG, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm,IDA-Boc, IDA-Ac, IDA-Isovaleric acid, ADA triazine, triazine-Boc,isophthalic acid, 1,3-phenylenediacetic acid, Glu, Asp, D-Glu, D-Asp,1,4-phenylenediacetic acid, biphenyl diacetic acid, cyclopropylaceticacid, succinic acid, glutaric acid, dodecanedioic acid, suitablealiphatic diacids, suitable aromatic diacids, heteroaromatics, andpolyethylene glycols having a molecular weight, for example, from 400 Dato 40,000 Da.

The individual IL-2Rα ligands can be linked in various ways to producehomodimers or homomers, heteromers, that can be evaluated for IL-2Ragonist and/or IL-2R antagonist activity. For example, homodimers ofIL-2Rα ligands or heteromers of an IL-2Rα ligand with IL-Rβ ligandand/or IL-2Rγc ligand can function as an IL-2R antagonist. Agonist andantagonist activity can depend on heteromers binding simultaneously toboth IL-2Rβ and IL-2Rγc subunits to induce proximity and orientationcompatible with signaling or inhibition. Several compoundcharacteristics can influence the activity of homodimers or heteromerssuch as, for example, the linker structure, the linker length, thepeptide ligand orientation, the ECD binding site-specificity of themonomeric peptides, and the affinities of each ligand for the respectivereceptor subunits. IL-2R agonist and IL-2R antagonist activity candepend on increasing the affinity of the IL-2Rα ligand to the IL-2Rαsubunit. Induced receptor subunit orientation and the potential forproper intra-cellular alignment and signaling can be, in part, afunction of the orientations in which the peptide ligands link to formthe heteromer. To determine suitable induced subunit orientations,adjacent IL-2R ligands can be linked in any of four (4) possibleorientations such that the C-termini of both subunit binding ligands arecoupled through a linker, the N-termini of both subunit binding ligandsare coupled through a linker, or the N-terminus of one binding subunitcan be bound through the C-terminus of the other binding subunit througha suitable linker. Homomers and heteromers can also be linked throughamino acid side chains. Heteromer linkage orientation can be engineered,for example, by synthesizing ligand monomers with the clickfunctionality, i.e., azide or alkyne, and PEG-linker on either theN-terminus or on the C-terminus.

A polypeptide can be a synthetically modified polypeptide comprising oneor more IL-2Rα ligands. The modifications can be influence, for example,the activity of the polypeptide or the pharmacokinetics of thepolypeptide. Examples include polypeptides incorporating polyethyleneglycol moieties or albumin binding moieties.

Compounds comprising an IL-2Rα ligand can be a fusion protein where thefusion partner is from a biological source. An IL-2Rα ligand can befused to another protein that imparts a desired functionality to theconstruct. For example, the protein can impart a desired pharmacokineticprofile or to target specific antigens.

Examples of suitable fusion partners include Fc fusion proteins, IgGfusion proteins, human serum albumin (HSA) fusion proteins, other humanproteins and mutants and/or variants thereof; and hydrophilic,biodegradable protein polymers. A fusion protein partner can be anaturally occurring protein, a modified-naturally occurring protein, ora synthetic protein.

For example, an IL-2Rα ligand provided by the present disclosure can befused to a protein that increases the circulating half-life of thecompound. Fusion of therapeutic proteins with IgG or IgG Fc domainsaccomplishes this by increasing the hydrodynamic radius of the protein,thus reducing renal clearance, and through Neonatal Fc Receptor(FcRn)-mediated recycling of the fusion protein, and thereby prolongingthe circulating half-life. Other fusion proteins can be designed tomodify properties such as the pharmacokinetics, biodistribution,pharmacodynamics, pharmacology, cytotoxicity, and/or targeting.

A fusion protein provided by the present disclosure can comprise apeptide, or multiple tandem peptides provided by the present disclosurelinked to one or more fusion protein partners. A fusion protein partnercan be linked to the N-terminus and/or the C-terminus of tandempeptides. One or more fusion protein partners can be linked to theN-terminus and/or the C-terminus of tandem peptides. An IL-2Rα ligandcan be linked to one or more fusion protein partners, where each of thefusion protein partners can be the same or some of the fusion proteinpartners can be different than other of the fusion protein partnerslinked to a peptide.

The amino acid sequence at the junction between an IL-2Rα ligand and afusion partner protein can be either a direct fusion of the two proteinsequences or a fusion with an intervening linker peptide. Linkerpeptides can be included as spacers between the two protein moieties.Linker peptides can promote proper protein folding and stability of thecomponent protein moieties, improve protein expression, and enablebetter bioactivity of the component protein moieties. Peptide linkersused in fusion proteins can be designed to be unstructured flexiblepeptides. Peptide linkers can be, for example, rich in glycine andserine, such as repeats of a sequence such as, for example, GS, GGS,GGGS (SEQ ID NO: 1039), or GGGGS (SEQ ID NO: 1040). A flexible linkerpeptide with a fully extended β-strand conformation can have anend-to-end length of approximately 3.5 Å per residue. Thus, a linkerpeptide of 5, 10, 15, 20 or more than 20 residues can have a maximumfully extended length of 17.5 Å, 35 Å, 52.5 Å, 70 Å, 140 Å, or more than140 Å, respectively.

A linker peptide can facilitate obtaining an appropriate conformationand orientation of individual fusion protein moieties to facilitate theengagement of the IL-2Rα ligand with the IL-2Rα subunit, facilitatebinding of the IL-2Rα ligand to the IL-2 receptor, enable fusion proteinrecycling, and prolong the circulating half-life of the active moiety.Because the factors influencing these interactions are difficult topredict, the requirement for and the proper length of a linker peptidemust be empirically tested and determined.

There are multiple options for the design and construction of a fusionprotein comprising an IL-2Rα ligand and which can be selected to obtaina compound having the desired biological activity and pharmaceuticalcharacteristics. Design options include, for example, the nature of theIL-2Rα ligand, the choice of the fusion partner protein moiety, theconfiguration of fusion partners in the fusion protein, and the aminoacid sequence at the junction between the IL-2Rα ligand and the fusionpartner protein.

In general, preparation of the fusion proteins provided by the presentdisclosure can be accomplished by recognized recombinant DNA techniquesinvolving, for example, polymerase chain amplification reactions (PCR),preparation of plasmid DNA, cleavage of DNA with restriction enzymes,preparation of oligonucleotides, ligation of DNA, isolation of mRNA,introduction of the DNA into a suitable cell, transformation ortransfection of a host, culturing of the host. Additionally, fusionproteins can be isolated and purified using chaotropic agents and wellknown electrophoretic, centrifugation and chromatographic methods.

Genes encoding fusion proteins provided by the present disclosureinvolve restriction enzyme digestion and ligation as the basic stepsemployed to yield DNA encoding the desired fusions. The ends of the DNAfragment may require modification prior to ligation, and this may beaccomplished by filling in overhangs, deleting terminal portions of thefragment(s) with nucleases (e.g., ExoIII), site directed mutagenesis, orby adding new base pairs by PCR. Polylinkers and adaptors can beemployed to facilitate joining of selected fragments. The expressionconstruct can be assembled in stages employing rounds of restriction,ligation, and transformation of E. coli. Numerous cloning vectorssuitable for construction of the expression construct are known in theart. The selection of a cloning vector can be influenced by the genetransfer system selected for introduction of the expression constructinto the host cell. At the end of each stage, the resulting constructmay be analyzed by restriction, DNA sequence, hybridization and PCRanalyses.

Site-directed mutagenesis can be used to introduce specific mutationsinto the genes encoding the fusion proteins provided by the presentdisclosure.

Various promoters (transcriptional initiation regulatory region) may beused. The selection of the appropriate promoter can depend on theproposed expression host. Promoters from heterologous sources may beused as long as they are functional in the chosen host.

Various signal sequences may be used to facilitate expression of thefusion proteins. Signal sequences can be selected or designed forefficient secretion and processing in the expression host may also beused. A signal sequence which is homologous to the human IL-2 codingsequence may be used for mammalian cells. The signal sequence may bejoined directly through the sequence encoding the signal peptidasecleavage site to the protein coding sequence, or through a shortnucleotide bridge.

Nucleic acids encoding a desired fusion protein can be introduced into ahost cell by standard techniques for transfecting cells.

Alternatively, one can use synthetic gene construction for all or partof the construction of the fusion proteins. This can entail in vitrosynthesis of a designed polynucleotide molecule to encode a polypeptidemolecule of interest. Gene synthesis can be performed utilizing a numberof techniques, such as the multiplex microchip-based technology andsimilar technologies wherein oligonucleotides are synthesized andassembled upon photo-programmable microfluidic chips.

Fusion proteins provided by the present disclosure can be isolated fromharvested host cells or from the culture medium.

Compounds comprising an IL-2Rα ligand provided by the present disclosureinclude compounds that act as IL-2Rαβγc agonists.

An IL-2Rαβγc agonist provided by the present disclosure can comprisesynthetic peptides or recombinant peptides linked in tandem to create asingle chain peptide comprising an IL-2Rα ligand, an IL-2Rβ ligand, andan IL-2Rγc ligand. The ligands can be in any order and can be separatedby amino acid linkers. The synthetic peptides can comprise natural aminoacids or peptides with natural amino acids and suitable substitutionswith unnatural amino acids. IL-2Rαβγc agonists provided by the presentdisclosure can be a recombinant fusion protein comprising an IL-2Rαligand, an IL-2Rβ ligand, and IL-2Rγc ligand and fusion partner such asan Fc protein, an IgG protein, human serum albumin or other natural ordesigned protein, or a hydrophilic, biodegradable protein polymer. AnIL-2Rαβγc agonist can comprise one or more IL-2Rα ligands. An IL-2Rαβγcagonist can comprise an IL-2Rα ligand, an IL-2Rβ ligand, and an IL-2Rγcligand and include one or more moieties selected to modify thepharmacokinetics of the IL-2Rαβγc agonist such as PEG or an albuminbinding moiety.

An IL-2Rαβγc agonist can bind to IL-2Rα and activate the IL-2 receptor.An IL-2Rαβγc agonist can bind to IL-2Rα with an IC₅₀, for example, lessthan 100 μM, less than 10 μM, less than 1 μM, less than 100 nM, lessthan 10 nM, or less than 1 nM. An IL-2Rαβγc agonist can bind to IL-2Rαeither competitively or non-competitively with IL-2.

An IL-2Rαβγc agonist comprising an IL-2Rα ligand, an IL-2Rβ ligand, andan IL-2Rγc ligand can be configured to more potently activate cellsexpressing the IL-2Rα subunit, thereby facilitating the ability todifferentially activate IL-2R expressed on the surface of different celltypes by controlling dose of the agonist. For example, when incubatedwith a heteromeric compound comprising an IL-2Rα ligand, IL-2Rβ ligand,and an IL-2Rγc ligand, primary human peripheral blood mononuclear cells(PBMC) expressing the IL-2Rαβγc subunit, phosphorylate transcription 5(STAT5) under conditions wherein human peripheral blood mononuclearcells (PBMC) expressing only the IL-2Rβγc subunits, do not phosphorylatetranscription 5 (STAT5) to the same degree. A heteromer can comprise anIL-2Rα ligand, IL-2Rβ ligand, an IL-2Rγc ligand, and a linker, where thelinker is configured such that the heteromer is an agonist for the IL-2receptor. A linker can comprise a length that facilitates binding of anIL-2Rα ligand, an IL-2Rβ ligand, and an IL-2Rγc ligand to the IL-2receptor. For example, a linker can have a length from 10 Å to 400 Å,from 10 Å to 300 Å, from 10 Å to 200 Å, 20 Å to 100 Å, from 30 Å to 80Å, or from 40 Å to 60 Å. A linker can comprise a chemical structure thatfacilitates simultaneous binding of an IL-2Rα ligand, an IL-2Rβ ligand,an IL-2Rγc ligand to the respective IL-2 receptor subunits. For example,a linker can comprise a peptide or a hydrocarbon.

An IL-2Rαβγc agonist can partially activate the IL-2 receptor. Partialactivation refers to a level of activation, that is, for example, lessthan 75% of maximum activation, less than 50%, less than 25%, less than10%, or less than 1% of the maximum activation. Maximum activation(E_(max)) is the amplitude of cellular signal (activation) achievable athigh agonist concentration such as a high concentration of IL-2. PartialIL-2Rαβγc agonists can be effective in modulating the levels of responseof IL-2R to activation by the IL-2Rβ and IL-2Rγc subunits amongdifferent cell types expressing IL-2R. For example, different cell typesare known to vary in expression levels of each of the IL-2R subunits,Rα, Rβ, and Rye, and to exhibit different sensitivities to IL-2Ragonists.

An IL-2R agonist comprising one or more IL-2Rα ligands can exhibitincreased binding and potency on cells expressing the IL-2Rα subunit(such as Tregs). Natural IL-2R agonists, or mutants and modified formsof natural IL-2R agonists such as IL-2, can be modified to includeadditional IL-2Rα ligands to further increase affinity and potency ofthese agonists on IL-2Rα expressing cells.

An IL-2Rαβγc agonist can comprise an IL-2Rα ligand and modified IL-2Rβand/or IL-2Rγc ligands. Modified IL-2Rβ and IL-2Rγc ligands can beselected or designed to bind and activate IL-2R, but with low or modestaffinity and potency to IL-2R. Such IL-2Rαβγc agonists can have greaterdifferential sensitivity for IL-2R activation between cells that highlyexpress IL-2Rα and cells having a low level of IL-2Rα expression. Forexamples, between Tregs that have a high expression of IL-2Rα and Teffcells that have a low expression level of IL-2Rα.

An IL-2Rαβγc agonist can comprise one or more IL-2Rα ligands. Thepresence of multiple IL-2Rα ligands can preferentially increase thepotency of the agonists on cells that highly express IL-2Rα compared tocells having low expression levels of IL-2Rα.

An IL-2Rαβγc agonist can comprise a moiety having an additionalpharmacological activity other than that mediated by activation of theIL-2 receptor. The pharmacological activity can be an activity that hasa therapeutic efficacy that is synergistic with that of the IL-2Rαβγcagonist or the pharmacological activity can be an activity that has atherapeutic efficacy that is not synergistic with that of the IL-2Rαβγcagonist. For example, a moiety or molecule having a usefulpharmacological activity can comprise a checkpoint inhibitor.

Compounds provided by the present disclosure include IL-2Rα antagonists.An IL-2Rα antagonist is a compound comprising an IL-2Rα ligand thatinhibits binding of IL-2 and mutants and modified forms thereof, to theIL-2Rα subunit and/or diminishes IL-2 activation of the IL-2 receptor.

IL-2Rα antagonists can attenuate the sensitivity of cells expressing theIL-2Rα subunit to activation by IL-2 or mutants and modified formsthereof. Examples of cells expressing the IL-2Rα subunit include Tregs.

IL-2Rα antagonists include compounds having more than one IL-2Rα ligandand can bind competitively or non-competitively with IL-2 to the IL-2receptor.

IL-2Rα antagonists can comprise one or more IL-2Rα ligands and a moietyhaving a useful pharmacological activity. The moiety can exhibit apharmacological activity that is synergistic with IL-2Rα inhibition oris not synergistic with inhibition of the IL-2Rα subunit.

IL-2Rα antagonists further include recombinant fusion proteins.

An IL-2R antagonist can comprise an IL-2Rα ligand only; an IL-2Rα ligandand an IL-2Rβ ligand; an IL-2Rα ligand and an IL-2Rγc ligand; or anIL-2Rα ligand, an IL-2Rβ ligand, and an IL-2Rγc ligand.

IL-2R antagonists include compounds that bind to either the IL-2Rαsubunit or to the IL-2Rβ or IL-2Rγc subunit and inhibit activation ofthe IL-2 receptor.

IL-2R antagonists include compounds that bind to the IL-2Rα subunit andto the IL-2Rβ and/or the IL-2Rγc subunits and inhibit activation of theIL-2 receptor, where the IL-2Rβ and IL-2Rγc ligands are configured tonot activate the IL-2 receptor. Such compounds are high affinityantagonists for IL-2R activation and the presence of an IL-2Rα ligandenhances the potency of the IL-2R antagonists.

IL-2R antagonists include compounds comprising the IL-2Rα and/or theIL-2Rβ and/or the IL-2Rγc ligands, which are configured to exhibitpartial activation of the IL-2 receptor. These compounds are examples ofpartial IL-2R agonists. Such compounds are useful for modulating thelevel of response of cells to IL-2R agonists among cells havingdifferent expression levels of IL-2R subunits. Use of the partial IL-2Ragonists/antagonists can modulate the response of cells to IL-2Ragonists among cells having different expression levels of the IL-2Rα,IL-2Rβ, and/or IL-2Rγc subunits.

An IL-2R antagonist can comprise one or more IL-2Rα ligands. An IL-2Rantagonist can be a peptide or a polypeptide, which can be synthetic orrecombinant. In addition to one or more IL-2Rα ligands, an IL-2Rantagonist can comprise one or more IL-2Rβ ligands and/or one or moreIL-2Rγc ligands. The IL-2R ligands can be coupled in any order, in anyorientation, and can be coupled with linkers. The linkers can comprisenatural and/or unnatural amino acids and/or non-peptidyl structures.

A peptidyl or polypeptidyl IL-2R antagonist can be chemically modifiedto include, for example, moieties that affect the pharmacokinetics ofthe IL-2R antagonist such as PEG and albumin-binding moieties.

IL-2R antagonists further include recombinant fusion proteins.

Compounds comprising an IL-2Rα ligand include diagnostic reagents. As adiagnostic agent, a compound comprising an IL-2Rα ligand can be used todetect and/or measure cells expressing the IL-2Rα ligand. The compoundscan be used to determine the expression level of the IL-2Rα expressionof a cell, or population of cells, or of a tissue. The compounds can beused to assess the binding affinity of the IL-2Rα subunits in a cell orpopulation of cells. The compounds may be used to determine the type ofcell, for example, based on IL-2Rα expression levels.

The compounds can be useful for in vitro and in vivo diagnostics.

A diagnostic compound comprising an IL-2Rα ligand can comprise adetectable marker. The detectable marker can be cleavable ornon-cleavable.

A detectable marker can comprise, for example, a radiolabel, afluorescent label, an enzymatic label.

A diagnostic compound comprising an IL-2Rα ligand can be used to measurecells expressing the IL-2Rα subunit and/or the level of expression ofcells expressing the IL-2Rα subunit in a biological sample such as asample of blood of a patient. Measurements can be made, for example,using flow cytometry. The number of cells expressing the IL-2Rα subunitand/or the expression level of the IL-2Rα subunit, when correlated witha disease in a patient or a pharmacologically significant parameter ofthe disease in a patient can be used to inform treatment of the disease.For example, if a level of expression of the IL-2Rα subunit is above orbelow a therapeutically meaningful threshold for a particular disease, acompound comprising an IL-2Rα ligand provided by the present disclosurecan be administered to the patient to treat the disease.

Compounds comprising an IL-2Rα ligand can be attached to a solidsupport. Based on their ability to bind to the IL-2Rα subunit, thecompounds can be used as reagents for detecting IL-2Rα subunits, forexample, on living cells, fixed cells, in biological fluids, in tissuehomogenates, in purified, and natural in biological materials. Inaddition, based on their ability to bind the IL-2Rα subunit, thepeptides of the present invention can be used, for example, in in situstaining, FACS (fluorescence-activated cell sorting), Western blotting,and ELISA. In addition, compounds provided by the present disclosure canbe used in receptor purification, or in purifying cells expressingIL-2Rα subunit on the cell surface.

Compounds comprising an IL-2Rα ligand provided by the present disclosurecan also be used as reagents for various medical research and diagnosticuses. Such uses include, for example, use as a calibration standard forquantitating the activities of candidate IL-2R agonists or IL-2Rantagonists in functional assays; use to maintain the proliferation andgrowth of IL-2-dependent cell lines; (3) use in structural analysis ofthe IL-2-receptor through co-crystallization; use to investigate themechanism of IL-2 signal transduction/receptor activation; and otherresearch and diagnostic applications wherein the IL-2-receptor isimplicated.

Assessing single patient response to therapy and qualifying a patientfor optimal therapy are among the greatest challenges of modernhealthcare and relate to trends in personalized medicine. A compoundcomprising an IL-2Rα ligand can have target selectivity for diseases inwhich cells associated with the etiology of the disease express theIL-2Rα ligand. For example, a compound comprising an IL-2Rα ligandradiolabeled for positron emission tomography (PET) or single photonemission computed tomography (SPECT) can be used to predict thetargeting of the treatment based on a single-study, case-by-case patientanalysis thus excluding subjects that are expected not to benefit fromtreatment with a therapeutic compound affecting the activity of theIL-2Rα subunit. PET/SPECT scans using radiolabeled a compound comprisingan IL-2Rα ligand, once correlated to the concentration of a compoundcomprising an IL-2Rα ligand can provide a three-dimensional distributionmap, which can then be used for macroscopic dose calculations.

Compounds comprising an IL-2Rα ligand can comprise one or more imagingagents. The IL-2Rα ligand can direct and localize the compound to cells,populations of cells, and tissue expressing the IL-2Rα subunit. Theimaging compounds can comprise one or more imaging agents such asradiolabels, fluorescent labels, enzymatic labels, or PET imagingagents.

The imaging agents can be used to determine the number of cellsexpressing the IL-2Rα subunit, the expression level of cells expressingthe IL-2Rα subunit, or properties of the IL-2Rα subunit such as theaffinity of the IL-2Rα subunit to a particular IL-2Rα ligand and/orcompound comprising an IL-2Rα ligand. The imaging agents can be used,for example, to evaluate cancer cells expressing the IL-2Rα receptor, orto evaluate Treg and/or Teff cells.

The label can be detected to determine a biodistribution of the compoundin a patient or to assess the potential for therapeutic efficacy. Forexamples, tumors expressing high levels of the IL-2R receptor and/or theIL-2Rα subunit may be attractive targets for compounds comprising anIL-2Rα ligand provided by the present disclosure.

The imaging agents can be used to evaluate cells expressing the IL-2Rαsubunit before therapy, during therapy, and/or following therapy.

Imaging agents comprising an IL-2Rα ligand can further comprise a moietycapable of binding to a cell surface and in particular to a proteinexpressed on the cell surface. The protein can be indicative of acertain cell type and is referred to as a cell surface marker. Imagingagents comprising both an IL-2Rα ligand and a cell surface marker can beused to assess cells, a population of cells, and/or a tissue expressingboth the IL-2Rα subunit and the cell surface marker. Assessment caninclude determining the number of cells expressing both the IL-2Rαsubunit and the cell surface marker, the expression levels of the IL-2Rαsubunit and the cell surface marker, and/or the affinity of the imagingagent to the IL-2Rα subunit and/or the cell surface marker.

Cells expressing both the IL-2Rα subunit and the cell surface marker canbe, for example, Tregs and/or activated Teff cells.

The imaging agents can be used to evaluate cells expressing the IL-2Rαsubunit and the cell surface marker before therapy, during therapy,and/or following therapy.

As a practical example, T cell infiltration of tumor lesions is a knownprognostic factor in several tumor types and is used as a treatmentmechanism in some of these tumor types. For example, in metastaticmelanoma, treatment with immune checkpoint inhibitors induces clinicalbenefit in about 30-50% of the patients. Tumor-infiltrating T cellsexpress the IL-2 receptor on their surface. Therefore, these T cells canbe visualized by molecular imaging with a compound comprising an IL-2Rαligand and a radiolabel such as a PET tracer.

As another example, IL-2 is synthesized and secreted by activated Tlymphocytes, especially CD8⁺ CTL and CD4⁺ Th1 lymphocytes. T lymphocyteactivation is observed in many types of inflammatory diseases, such asinflammatory degenerative diseases, graft rejection, tumor inflammation,organ-specific autoimmune diseases, and adipose inflammatory insulinresistance. IL-2 binds with high affinity to the cell membrane IL-2receptor, which is mainly expressed on the cell surface of activated Tlymphocytes. PET imaging of activated T lymphocytes by a radiolabeledcompound comprising an IL-2Rα ligand therefore provides an in vivo,dynamic approach in studying the immune-cell infiltration in theseinflammatory diseases.

Compounds comprising IL-2Rα ligands can comprise a cell-specifictargeting moiety or molecule.

A cell-specific targeting moiety can comprise a moiety that has anaffinity for a component on the surface of a cell such as a receptor, aprotein, or an epitope. A moiety can comprise, for example, a ligand oran antibody having an affinity to a cell surface component.

The targeting moiety can direct and concentrate compounds comprising anIL-2Rα ligand at the cells, population of cells, or tissue targeted bythe targeting moiety.

The targeting moiety can enhance the potency of IL-2R agonism or IL-2Rantagonism for the cells or population of cells being targeted.

The targeting moiety can provide a differential response to IL-2Ragonism or to IL-2R antagonism between the cells being targeted and thecells not being targeted by the targeting moiety.

The targeting moiety can provide a differential response to IL-2Ragonism or IL-2R antagonism between cells having a high expression levelof the targeted component and cells having a lower expression level ofthe targeted component.

Compounds comprising an IL-2Rα ligand can further comprise a bioactivemoiety or a bioactive molecule. A compound comprising an IL-2Rα ligandcan be used to deliver the bioactive moiety or bioactive molecule tocells, to a population of cells, or to a tissue expressing the IL-2Rαsubunit.

The bioactive moiety or molecule can be non-cleavable and capable ofexerting a biological activity when bound to the compound comprising anIL-2Rα ligand.

The bioactive moiety or molecule can be cleavable. The moiety can becleavable by any suitable mechanism such as by pH, enzymatic, thermal,and/or electromagnetic mechanisms. Electromagnetic mechanisms include,for example, exposing the compounds to infrared, visible, or ultravioletradiation, where the bioactive moiety is attached to the compoundscomprising an IL-2Rα ligand through a photolabile moiety capable ofbeing cleaved by the radiation.

The bioactive molecule can be non-cleavable but otherwise activatable,such as for example, activatable by exposure to electromagneticradiation.

IL-2Rα ligands can be selected to have enhanced binding to the IL-2Rαsubunit at a certain pH. For example, a pH-selective IL-2Rα ligand canhave a greater affinity to the IL-2Rα subunit at low pH commensuratewith that of a solid tumor microenvironment. Compounds comprising low-pHselective IL-2Rα ligands can be used to preferentially target cells inlow pH environments expressing the IL-2Rα subunit compared to cells innormal pH environments associated with healthy tissue.

Thus, compounds comprising selective IL-2Rα ligands such as pH-selectiveIL-2Rα ligands can be used to deliver bioactive moieties and moleculesto cells targeted by the selective IL-2Rα ligands.

A bioactive moiety or bioactive molecule can itself be selective for aparticular cell population. For example, a bioactive moiety or bioactivemolecule can exhibit a greater or lesser affinity, potency, and/oractivity at the cell being targeted by a selective or IL-2Rα ligand. Forexample, the bioactive moiety or molecule can exhibit greaterbioactivity in a low pH tumor microenvironment when targeted by apH-selective IL-2Rα ligand. In this example, the bioactive moiety isdirected to cells located in the low-pH tumor microenvironment thatexpress the IL-2Rα subunit by the pH-selective IL-2Rα ligand. Thus, theactivity of the pH-selective bioactive moiety is enhanced in the low-pHtumor microenvironment.

Compounds comprising an IL-2Rα ligand can further comprise a cytotoxicmoiety or molecule. Such compounds can be used to deliver a cytotoxiccompound to a cell expressing the IL-2Rα subunit such as Tregs. Thecytotoxic moiety or molecule can exert cytotoxicity when bound to thecompound or can be cleavable and the moiety or molecule can be cytotoxicwhen released from the compound; or the cytotoxic moiety can beactivated by electromagnetic radiation.

The cytotoxic moiety or molecule can be used to deplete cells expressingthe IL-2Rα ligand being targeted.

IL-2Rα ligand-containing cytotoxic compounds can have more than oneIL-2Rα subunit and thereby can exhibit a higher affinity and/orselectivity to cells, populations of cells, and tissue that highlyexpress the IL-2Rα subunit compared to cells having a lower expressionlevel of the IL-2Rα subunit.

IL-2Rα ligand-containing cytotoxic compounds can further include a cellsurface targeting component. Such cytotoxic compounds can exhibitenhanced efficacy to cells, populations of cells, and tissue expressingboth the IL-2Rα subunit and the surface target component.

Examples of suitable cytotoxic molecules include anti-microtubuleagents, alkylating agents, and DNA minor groove binding agents.

These therapeutic strategies for targeting IL-2Rα expressing cells withcytotoxic compounds have been demonstrated.

As an example, denileukin diftitox (DAB-IL-2, Ontak) is adiphtheria-toxin-based fusion protein that depletes CD25-positive cellsincluding regulatory T cells and has been approved for the treatment ofpersistent or recurrent cutaneous T cell lymphoma. Significanttoxicities of the drug include acute hypersensitivity, vascular leaksyndrome and impaired immune function. The latter two toxicities are dueto nonspecific binding of immunotoxin to macrophages and activatedlymphocytes. A modified immunotoxin was developed to the efficacy andreduce the toxicity. A modified diphtheria toxin (DT) served as thecytotoxic moiety and IL-2 served as the targeting moiety for targetingcancer cells that overexpress the IL-2 receptor. T cells, B cells,macrophages and natural killer cells express the IL-2Rβ and IL-2Rγcsubunits, whereas the IL-2Rα subunit is uniquely expressed on cancercells and activated T cells. Targeting the IL-2Rα subunit eliminatedtoxicity.

Cytotoxicity of this recombinant protein was observed to be more thandenileukin diftitox for cells with higher IL-2Rα expression whereas incells expressing both IL-2Rα subunit and the IL-2Rβ subunit,cytotoxicity varies from cell line to cell line. The immunotoxinexhibited comparable efficacy to denileukin diftitox and was morespecifically targeted to cells expressing the IL-2Rα subunit. The fusionprotein depletes IL-2Rα-positive cells including Tregs and has beenapproved for the treatment of persistent or recurrent cutaneous T celllymphoma.

Another example of an IL-2Rα-targeted cytotoxic compound is⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody for treating relapsedHodgkin's lymphoma. Using the anti-CD25 monoclonal antibody, daclizumabwas directed toward nonmalignant T cells expressing the IL-2Rα subunit,rather than the tumor cells. ⁹⁰Y provided strong β emissions that killedantigen-non-expressing tumor cells at a distance by a crossfire effect.Furthermore, the strong Pirradiation killed normal cells in the tumormicroenvironment that nurture the malignant cells in the lymphomatousmass and thereby provided meaningful treatment of the Hodgkin'slymphoma.

Compounds comprising an IL-2Rα ligand can further comprise a moietyhaving a useful pharmacological activity.

The pharmacological moiety can function synergistically with IL-2Ragonist activity or synergistically with IL-2R antagonist activity, orthe pharmacological moiety may not exhibit synergism with activity ofthe IL-2Rα subunit.

Examples of suitable pharmacological moieties include antibodies andantibody fragments that are inhibitors of checkpoint molecules,pro-apoptotic and anti-apoptotic molecules, cytotoxic molecules,agonists of chemokine, antagonists of chemokine, cytokine, growth factorand other cell surface rectors, and ligands and inhibitors of cellsurface adhesion molecules such as integrins.

Peptides provided by the present disclosure can be synthesized bymethods known in the art, for example, by using standard solid phasetechniques.

A peptide comprising an IL-2Rα ligand provided by the present disclosurecan be modified, for example, by phosphorylation, and by other methodsknown in the art. Thus, the peptides provided by the disclosure can alsoserve as a basis to prepare peptide mimetics with similar biologicalactivity.

A variety of techniques are available for constructing peptide mimeticswith the same or similar desired biological activity as a correspondingpeptide but with more favorable activity than the peptide with respectto solubility, stability, and susceptibility to hydrolysis andproteolysis.

Pharmaceutical compositions provided by the present disclosure comprisea compound comprising an IL-2Rα ligand.

Pharmaceutical compositions provided by the present disclosure cancomprise a therapeutically effective amount of a compound comprising anIL-2Rα ligand or a pharmaceutically acceptable salt thereof togetherwith a suitable amount of one or more pharmaceutically acceptablevehicles so as to provide a composition for administration to a patient.Suitable pharmaceutical vehicles and methods of preparing pharmaceuticalcompositions are known.

A pharmaceutical composition can comprise a therapeutically effectiveamount of one or more compounds comprising an IL-2Rα ligand.

A compound comprising an IL-2Rα ligand and/or pharmaceutical compositionthereof can be used in an amount effective to achieve an intendedpurpose. For example, for use to treat a disease such as cancer or anautoimmune disease, a compound comprising an IL-2Rα ligand and/orpharmaceutical compositions thereof, can be administered atherapeutically effective amount for treating the cancer or theautoimmune disease.

The amount of a compound comprising an IL-2Rα ligand and/orpharmaceutical composition thereof that will be effective in thetreatment of a particular disease can depend on, among other factors,the patient being treated, the severity of the disease, the etiology ofthe disease, the manner of administration and the judgment of theprescribing physician, and can be determined by standard clinicaltechniques known in the art.

A therapeutically effective dose of a compound comprising an IL-2Rαligand and/or pharmaceutical composition thereof can provide atherapeutic benefit without causing substantial toxicity. Toxicity of acompound comprising an IL-2Rα ligand and/or pharmaceutical compositionsthereof may be determined using standard pharmaceutical procedures. Thedose ratio between toxic and therapeutic effect is the therapeuticindex. A compound comprising an IL-2Rα ligand and/or pharmaceuticalcomposition thereof can exhibit a high therapeutic index in treating adisease such as cancer or an autoimmune disease. A dose of a compoundcomprising an IL-2Rα ligand and/or pharmaceutical composition thereofcan be within a range of circulating concentrations that include aneffective dose with minimal toxicity.

A dose of a compound comprising an IL-2Rα ligand provided by the presentdisclosure and appropriate dosing intervals may be selected to maintaina sustained therapeutically effective concentration of the compoundcomprising an IL-2Rα ligand provided by the present disclosure in theblood of a patient, and in certain embodiments, without exceeding aminimum adverse concentration.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound comprising an IL-2Rα ligand provided by thepresent disclosure. Such compounds may be provided, for example, totreat the disease being treated with a compound comprising an IL-2Rαligand or to treat a disease, disorder, or condition other than thedisease being treated with the compound comprising an IL-2Rα ligand, totreat a side-effect caused by administering the compound comprising anIL-2Rα ligand, to augment the efficacy of the a compound comprising anIL-2Rα ligand, and/or to modulate the activity of the compoundcomprising an IL-2Rα ligand.

A compound comprising an IL-2Rα ligand provided by the presentdisclosure may be used in combination with at least one othertherapeutic agent. A compound comprising an IL-2Rα ligand may beadministered to a patient together with another compound for treatingthe disease. The at least one other therapeutic agent may be a differentcompound comprising an IL-2Rα ligand. A compound comprising an IL-2Rαligand and the at least one other therapeutic agent may act additivelyor synergistically. The at least one additional therapeutic agent may beincluded in the same pharmaceutical composition or vehicle comprisingthe compound comprising an IL-2Rα ligand or may be in a separatepharmaceutical composition or vehicle. Accordingly, methods provided bythe present disclosure further include, in addition to administering acompound comprising an IL-2Rα ligand, administering one or moretherapeutic agents effective for treating the disease being treated bythe compound comprising an IL-2Rα ligand or a different disease. Methodsprovided by the present disclosure include administration of a compoundcomprising an IL-2Rα ligand and one or more other therapeutic agentsprovided that the combined administration does not inhibit thetherapeutic efficacy of the compound comprising an IL-2Rα ligand and/ordoes not produce adverse combination effects. A pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand providedby the present disclosure may be administered with one or moresubstances, for example, to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, and/orstability, of the compound comprising an IL-2Rα ligand. For example, apharmaceutical composition comprising a compound comprising an IL-2Rαligand can be co-administered with an active agent havingpharmacological effects that enhance the therapeutic efficacy of thecompound comprising an IL-2Rα ligand.

Compounds comprising an IL-2Rα ligand provided by the present disclosureor a pharmaceutical composition thereof may be included in a kit thatmay be used to administer the compound to a patient for therapeuticpurposes. A kit may include a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand provided by the present disclosuresuitable for administration to a patient and instructions foradministering the pharmaceutical composition to the patient. The kit canbe a kit, for example for treating cancer or a kit for treating anautoimmune disease. A kit for use in treating cancer or an autoimmunedisease in a patient can comprise a compound comprising an IL-2Rα ligandprovided by the present disclosure, a pharmaceutically acceptablevehicle for administering the compound, and instructions foradministering the compound to a patient.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration. Instructionssupplied with a kit may be printed and/or supplied, for example, as anelectronic-readable medium, a video cassette, an audiotape, a flashmemory device, or may be published on an internet web site ordistributed to a patient and/or health care provider as an electroniccommunication.

Compounds comprising an IL-2Rα ligand provided by the present disclosuremay be used for treating cancer in a patient. The cancer can be, forexample, a solid tumor or a metastasis.

A compound comprising an IL-2Rα ligand provided by the presentdisclosure or a pharmaceutical composition thereof may be administeredto treat a cancer known to be treated by activation or inhibition of theIL-2R receptor. Compounds comprising an IL-2Rα ligand provided by thepresent disclosure or a pharmaceutical composition thereof may beadministered to treat a cancer known to be treated by activation orinhibition of the IL-2Rβγc subunits and where simultaneous activation ofthe IL-2Rα subunit enhances therapeutic efficacy, modulates therapeuticefficacy, enhances selective therapeutic efficacy, and/or minimizesunwanted side effects.

Compounds comprising an IL-2Rα ligand provided by the present disclosureor a pharmaceutical composition thereof can be used to treat, forexample, one or more of the following cancers: acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, appendixcancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cellcarcinoma (nonmelanoma), B-cell lymphoma, bladder cancer, bone cancer,brain and spinal cord tumors, brain stem cancer, brain tumor, breastcancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, carcinomaof head and neck, central nervous system embryonal tumors, cerebellarastrocytoma, cerebral astrocytoma/malignant glioma, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia,colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,desmoplastic small round cell tumor, ductal carcinoma, dye cancer,endocrine pancreas tumors (islet cell tumors), endometrial cancer,ependymoblastoma, esophageal cancer, esthesioneuroblastoma, Ewing familyof tumors, extracranial germ cell tumor, extrahepatic bile duct cancer,gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor, gestational trophoblastic tumor,glioblastoma, glioma, hairy cell leukemia, head and neck cancer, heartcancer, hematopoetic tumors of the lymphoid lineage, hepatocellularcancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visualpathway glioma, IDs-related lymphoma, intraocular melanoma, islet celltumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis,laryngeal cancer, leukemia, lip and oral cavity cancer, male breastcancer, malignant fibrous histiocytoma, malignant germ cell tumors,malignant mesothelioma, medulloblastoma, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, multiple endocrine neoplasiasyndrome, multiple myeloma, mycosis fungoides, myelodysplastic,myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-smallcell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma,ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor,ovarian low malignant potential tumor, pancreatic cancer, pancreaticneuroendocrine tumors (islet cell tumors), papillomatosis,paraganglioma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pharyngeal cancer, pheochromocytoma, pinealparenchymal tumors, pineoblastoma and supratentorial primitiveneuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiplemyeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primarycentral nervous system lymphoma, primary liver cancer, primarymetastatic squamous neck cancer with occult, prostate cancer, rectalcancer, renal cell cancer, renal pelvis and ureter, respiratory tractcarcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,sarcoma, Sézary syndrome, skin cancer, skin cancer, small intestinecancer, soft tissue sarcoma, squamous cell carcinoma (nonmelanoma),stomach cancer, supratentorial primitive neuroectodermal tumors, T-celllymphoma, testicular cancer, throat cancer, thymoma and thymiccarcinoma, thyroid cancer, transitional cell cancer, urethral cancer,uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma,vulvar cancer, Waldenström macroglobulinemia, Wilms tumor, and systemicand central metastases of any of the foregoing.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to be effective in treatingcancer in a patient, such as the same cancer being treated with thecompound comprising an IL-2Rα ligand.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositionthereof may be administered in conjunction with a chemotherapeuticagent, such as, for example, N-acetyl cysteine (NAC), adriamycin,alemtuzumab, amifostine, arsenic trioxide, ascorbic acid, bendamustine,bevacizumab, bortezomib, busulfan, buthionine sulfoxime, carfilzomib,carmustine, clofarabine, cyclophosphamide, cyclosporine, cytarabine,dasatinib, datinomycin, defibrotide, dexamethasone, docetaxel,doxorubicin, etoposide, filgrastim, floxuridine, fludarabine,gemcitabine, interferon alpha, ipilimumab, lenalidomide, leucovorin,melphalan, mycofenolate mofetil, paclitaxel, palifermin, panobinostat,pegfilrastim, prednisolone, prednisone, revlimid, rituximab, sirolimus,sodium 2-mercaptoethane sulfonate (MESNA), sodium thiosulfate,tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan,velcade, or a combination of any of the foregoing.

A compound comprising an IL-2Rα ligand and/or pharmaceutical compositionthereof can be used in combination therapy with other chemotherapeuticagents including one or more antimetabolites such as folic acid analogs;pyrimidine analogs such as fluorouracil, floxuridine, and cytosinearabinoside; purine analogs such as mercaptopurine, thiogunaine, andpentostatin; natural products such as vinblastine, vincristine,etoposide, tertiposide, dactinomycin, daunorubicin, doxurubicin,bleomycin, mithamycin, mitomycin C, L-asparaginase, and interferonalpha; platinum coordination complexes such as cis-platinum, andcarboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones andantagonists such as prednisone, hydroxyprogesterone caproate,medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol,ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone,flutamide, and leuprolide, anti-angiogenesis agents or inhibitors suchas angiostatin, retinoic acids, paclitaxel, estradiol derivatives, andthiazolopyrimidine derivatives; apoptosis prevention agents; triptolide;colchicine; luliconazole; and radiation therapy.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising compound comprising an IL-2Rα ligand may be administered inconjunction with one or more chemotherapeutic agents, such as, forexample, abarelix, abiraterone, abiraterone acetate, n-acetyl cysteine,aclarubicin hydrochloride, adriamycin, adenine, afatinib, afatinibdimaleate, alemtuzumab, alendronate sodium, alitretinoin, allopurinolsodium, altretamine, amifostine, aminoglutethimide, aminolevulinic acid,amrubicin, amsacrine, anastrozole, angiostatin, apremilast, aprepitant,arsenic trioxide, ascorbic acid, 1-asparaginase, azacitidine,azathioprine sodium, bazedoxifene (serm), belinostat, bendamustine hcl,o6-benzylguanine (o6-bg), bevacizumab, bexarotene, bicalutamide,biricodar, bleomycin sulfate, bortezomib, bosutinib, brivudine,buserelin, busulfan, buthionine sulfoxime, cabazitaxel, cabozantinib,capecitabine, carboplatin, carboquone, carfilzomib, carmofur,carmustine, ceritinib, chlorambucil, cisplatin, cladribine, clodronatedisodium, clofarabine, crizotinib, cyclophosphamide, cyclosporine,cytarabine, cytosine arabinoside, dabrafenib, dacarbazine, dactinomycin,dasatinib, datinomycin, daunorubicin, decitabine, defribrotide,degarelix acetate, dexamethasone, dexrazoxane hydrochloride, diaziquone,diethyl stilbestrol, docetaxel, doxifluridine, doxorubicinhydrochloride, doxorubicin free base, dromostanolone propionate,dutasteride, eltrombopag, enzalutamide, epirubicin hydrochloride,eribulin mesylate, erlotinib hydrochloride, estramustine phosphatesodium, ethinyl estradiol, etoposide phosphate, etoposide, everolimus,exemestane, fentanyl, filgrastim, fingolimod, floxuridine, fludarabinephosphate, fluorouracil, fluoxymesterone, flutamide, formestane,formylmelphalan, fosaprepitant, fotemustine, fulvestrant, gefitinib,gemcitabine hydrochloride, gemcitabine free base, glutathione,glyciphosphoramide, glyfosfin, goserelin acetate, granisetronhydrochloride, heptaplatin, hexyl 5-aminolevulinate, histrelin acetate,hydroxyprogesterone caproate, hydroxyurea, ibandronate sodium,ibrutinib, icotinib, idarubicin HCl, idelalisib, idoxuridine,ifosfamide, interferon alpha, imatinib mesylate, imiquimod, ingenolmebutate, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotideacetate, lapatinib free base, lapatinib ditosylate, lasofoxifene,lenalidomide, letrozole, leucovorin calcium, leuprolide acetate,levamisole hydrochloride, levoleucovorin calcium, iobenguane,lobaplatin, lomustine, maropitant, masoprocol, mechlorethaminehydrochloride, megestrol acetate, medroxyprogesterone acetate, melphalanhydrochloride, mercaptopurine, mercaptoethane sulfonate sodium,methotrexate, methoxsalen, methyl aminolevulinate, methylene blue,methylisoindigotin, mifamurtide, miltefosine, miriplatin, mithamycin,mitobronitol, mitomycin C, mitotane, mitoxantrone hydrochloride,mycophenolate mofetil, nabiximols, nafarelin, nandrolone, nedaplatin,nelarabine, netupitant, nilotinib, nilutamide, nimustine, nintedanib,nocodazole, octreotide, olaparib, omacetaxine mepesuccinate, ondansetronhydrochloride, oxaliplatin, paclitaxel, palbociclib, palifermin,palonosetron hydrochloride, pamidronate disodium, panobinostat,pasireotide, pazopanib hydrochloride, pegfilrastim, pemetrexed disodium,pentostatin, peplomycin, pipobroman, pirarubicin, plerixafor,plicamycin, pomalidomide, ponatinib, porfimer sodium, porfiromycin,pralatrexate, prednimustine, prednisolone, prednisone, procarbazinehydrochloride, quinagolide hydrochloride, raloxifene, raltitrexed,radotinib, ranimustine, retinoic acids, revlimide, rituxinab,romidepsin, ruxolitinib, ruxolitinib phosphate, semustine, sirolimus,sodium thiosulfate, sorafenib free base, sorafenib tosylate,streptozocin, sufentanil, sunitinib, tacrolimus, talaporfin sodium,tamibarotene, tamoxifen citrate, tapentadol, temoporfin, temozolomide,temsirolimus, teniposide, teriflunomide, tertiposide, testolactone,testosterone propionate, thalidomide, thioguanine, thiotepa,thymalfasin, toceranib phosphate, topotecan hydrochloride, toremifenecitrate, trabectedin, trametinib, tretinoin, trilostane, triptorelin,tropisetron, uramustine, valrubicin, vandetanib, vedotin, vemurafenib,verteporfin, vinblastine, vincristine sulfate, vincristine free base,vindesine, vinorelbine tartrate, vorinostat, and zoledronic acid.

Compounds provided by the present disclosure can be useful in treatingautoimmune diseases. Autoimmune diseases are defined as human diseasesin which the immune system attacks its own proteins, cells, and tissues.A comprehensive listing and review of autoimmune diseases can be found,for example, in The Autoimmune Diseases (Rose and Mackay, 2014, AcademicPress).

Examples of autoimmune diseases include Addison's disease,agammaglobulinemia, alopecia areata, amyloidosis, ankylosingspondylitis, anti-GBM/anti-TBN nephritis, antiphospholipid syndrome,autoimmune angioedema, autoimmune dysautonomia, autoimmuneencephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease,autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy,autoimmune urticaria, axonal and neuronal neuropathy, Balo disease,Bechet's disease, benign mucosal pemphigoid, bullous pemphigoid,Castleman disease, celiac disease, Chagas disease, chronic inflammatorydemyelinating polyneuropathy, chronic recurrent multifocalosteomyelitis, Churg-Strauss, cicatricial pemphigoid, Cogan's syndrome,cold agglutinin disease, congenital heart block, Coxsackie myocarditts,CREST syndrome, Crohn's disease, dermatitis herpetiformis,dermatomyositis, Devic's disease, discoid lupus, Dressler's syndrome,endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome,fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cellmyocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosiswith polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimotothyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpesgestationis or pemphigoid gestationis, hypogammaglobulinemia, IgAnephropathy, IgG4-related sclerosing disease, immune thrombocytopenicpurpura, inclusion body myositis, interstitial cystitis, juvenilearthritis, juvenile diabetes, juvenile myositis, Kawasaki disease,Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus,lichen sclerosis, ligneous conjunctivitis, linear IgA disease, lupus,Lyme disease chronic, Meniere's diseases, microscopic polyangiitis,mixed connective tissue disease, Mooren's ulcer, Mucha-Habermanndisease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy,neuromyelitis, optica, neutropenia, ocular cicatricial pemphigoid, opticneuritis, palindromic rheumatism, PANDAS, paraneoplastic cerebellardegeneration, paroxysmal nocturnal hemoglobinuria, Parry Rombergsyndrome, pars planitis, Parsonage-Turner syndrome, pemphigus,peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polyglandular syndromes,polymyalgia rheumatica, polymyositis, postmyocardial infarctionsyndrome, postpericardiotomy syndrome, primary biliary cirrhosis,primary sclerosing cholangitis, progesterone dermatitis, psoriasis,psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum,Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy,relapsing polychondritis, restless legs syndrome, retroperitonealfibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidtsyndrome, scleritis, scleroderma, Sjogren's syndrome, sperm andtesticular autoimmunity, stiff person syndrome, subacute bacterialendocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu'sarteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Huntsyndrome, transverse myelitis, Type 1 diabetes, ulcerative colitis,undifferentiated connective tissue disease, uveitis, vasculitis,vitiligo, and Wegener's granulomatosis.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to be effective in treatingan autoimmune disease in a patient.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an IL-15 agonist for treating an autoimmune disease.For example, a suitable IL-15 agonist is disclosed in PCT InternationalPublication No. WO 2017/062832 A1 and in PCT International PublicationNo. WO 2015/153753 A1.

Compounds comprising an IL-2Rα ligand provided by the present disclosureand pharmaceutical compositions thereof may be administered to a patientto treat a disease associated with the activation, proliferation,metabolism, and/or differentiation of T-cells.

Compounds comprising an IL-2Rα ligand provided by the present disclosureand pharmaceutical compositions thereof may be administered to a patientto treat an organ transplant.

Compounds comprising an IL-2Rα ligand provided by the present disclosureand pharmaceutical compositions thereof may be administered to treat aninflammatory disease.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere with cellproliferation.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere withmetabolism. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interferewith mitochondrial metabolism. A compound comprising an IL-2Rα ligand ora pharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to be an anti-metabolite. A compound comprising an IL-2Rαligand or a pharmaceutical composition comprising a compound comprisingan IL-2Rα ligand may be administered in conjunction with an agent knownor believed to interfere RNA transcription. A compound comprising anIL-2Rα ligand or a pharmaceutical composition comprising a compoundcomprising an IL-2Rα ligand may be administered in conjunction with anagent known or believed to interfere with RNA translation. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interfere with protein synthesis. Acompound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere with synthesisof precursors for DNA synthesis and replication. A compound comprisingan IL-2Rα ligand or a pharmaceutical composition comprising a compoundcomprising an IL-2Rα ligand may be administered in conjunction with anagent known or believed to interfere with purine synthesis. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interfere with nucleoside synthesis.A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interact with mTOR. Acompound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interact be an mTORinhibitor. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interferewith cell cycle checkpoints.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with a checkpoint inhibitor including CTLA-4 inhibitors suchas ipilimumab, PD1 inhibitors such as pembrolizumab and cemiplimab, andPD-LI inhibitors such as atezolizumab, avelumab, and durvalumab. Acompound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an immunomodulator such as CD137/4-1BB, CD27, GIYR,and/or OC40.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to be cytotoxic. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to be cytostatic. A compound comprisingan IL-2Rα ligand or a pharmaceutical composition comprising a compoundcomprising an IL-2Rα ligand may be administered in conjunction with anagent known or believed to cause DNA damage. A compound comprising anIL-2Rα ligand or a pharmaceutical composition comprising a compoundcomprising an IL-2Rα ligand may be administered in conjunction with anagent known or believed to cause cell cycle arrest. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to cause mitotic catastrophe.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to modulate drug resistance.A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to reduce multi-drugresistance. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interactwith membrane proteins. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to interact with plasma membrane proteins. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interact with nuclear membraneproteins. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interactwith major vault protein or proteins. A compound comprising an IL-2Rαligand or a pharmaceutical composition comprising a compound comprisingan IL-2Rα ligand may be administered in conjunction with an agent knownor believed to interact with gen products of the MVP (major vaultprotein) gene.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to modulate glutathioneconcentration. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to modulate glutathione concentration within cells. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to decrease glutathione concentrationwithin cells. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to reduceglutathione uptake into cells. A compound comprising an IL-2Rα ligand ora pharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to reduce glutathione synthesis. A compound comprising anIL-2Rα ligand or a pharmaceutical composition comprising a compoundcomprising an IL-2Rα ligand may be administered in conjunction with anagent known or believed to reduce glutathione synthesis within cells.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere withneovascularization. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to reduce neovascularization. A compound comprising an IL-2Rαligand or a pharmaceutical composition comprising a compound comprisingan IL-2Rα ligand may be administered in conjunction with an agent knownor believed to promote neovascularization.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere with hormonehomeostasis. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interferewith hormone synthesis. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to interfere with hormone receptor binding. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interfere with hormone signaltransduction.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere with growthfactor homeostasis. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to interfere with growth factor synthesis. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interfere with growth factor receptorexpression. A compound comprising an IL-2Rα ligand or a pharmaceuticalcomposition comprising a compound comprising an IL-2Rα ligand may beadministered in conjunction with an agent known or believed to interferewith growth factor binding to growth factor receptors. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to interfere with growth factors bindingto growth factor receptors. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to interfere with growth factor receptor signal transduction. Acompound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with an agent known or believed to interfere with theHedgehog (Hh) signaling. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand can be administered in conjunction with an agent known orbelieved to inhibit the Hedgehog pathway signaling. A compoundcomprising an IL-2Rα ligand or a pharmaceutical composition comprising acompound comprising an IL-2Rα ligand may be administered in conjunctionwith an agent known or believed to inhibit ALK (anaplastic lymphomakinase) pathway signaling. A compound comprising an IL-2Rα ligand or apharmaceutical composition comprising a compound comprising an IL-2Rαligand may be administered in conjunction with an agent known orbelieved to inhibit non-homologous end joining (NHEJ) is a pathway.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a compound comprising an IL-2Rα ligand may be administered inconjunction with one or more agents known or believed to be a VEGFR(vascular endothelial growth factor receptor) inhibitor, a RTK (receptortyrosine kinase) inhibitor, a sodium channel current blocker, aFAK(focal adhesion kinase) inhibitor, a GLI (glioma-associated oncogene)inhibitor, a GLI1 inhibitor, a GLI2 inhibitor, a GLI3 inhibitor, a MAPK(mitogen-activated protein kinase) inhibitor, a MAPK/ERK pathway (alsoknown as Ras-Raf-MEK-ERK pathways) inhibitor, a MEK1 inhibitor, a MEK2inhibitor, a MEK5 inhibitor, a MEK5/ERK5 inhibitor, aRTA (renal tubularacidosis) inhibitor, a ALK (anaplastic lymphoma kinase) inhibitor, Aa LKkinase inhibitor, a nuclear translocation inhibitor, a PORCN (porcupine)inhibitor, a 5-ARI (5α-reductase inhibitor), topoisomerase inhibitor, aRas (rat sarcoma) inhibitor, a K-ras inhibitor, a CERK (ceramide kinase)inhibitor, a PKB (protein kinase B, also known as AKT) inhibitor, a AKT1inhibitor, EZH2 (enhacer of zeste homolog 2) inhibitor, a BET(bromodomain and extraterminal domain motif) inhibitor, a SYK (apleentyrosine kinase) inhibitor, JAK (janus kinase) inhibitors, a SYK/JAKinhibitor, a IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitor, a IDO1inhibitor, a RXR (retinoic X receptors) activating agent, a selectivelyRXR activating agent, a p-glycoprotein inhibitor, a ERK inhibitor, aPI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitor, a BRD(bromodomain-containing protein) inhibitor, a BRD2 inhibitor, a BRD3inhibitor, a BRD4 inhibitor, a BRDT (bromodomain testis-specificprotein) inhibitor, a reverse transcriptase inhibitor, a NRT (nucleosideanalog reverse-transcriptase) inhibitor, a PIM (proviral integrations ofmoloney virus) inhibitor, a EGFR (epidermal growth factor receptor)inhibitor, a photosensitizer, a radiosensitizer, a ROS (proto-oncogene,recptor tyrosine kinase) inhibitor, a ROS1 (proto-oncogene 1) inhibitor,a CK (caseine kinase) inhibitor, a CK2 inhibitor, a Bcr-Abl (breakpointcluster region—Abelson proto-oncogene) tyrosine-kinase inhibitor such asdasatinib, a microtubule stabilizing agent, a microtubuledepolymerisation/disassembly inhibitor, a DNA intercalator, an androgenreceptor antagonist, a chemoprotective agents, a HDAC (histonedeacetylase) inhibitor, a DPP (dipeptidyl pepdidase) inhibitor, a DPP-4inhibitor, BTK (Bruton's tyrosine kinase) inhibitor, a kinase inhibitorsuch as imatinib, a tyrosine kinase inhibitor such as nilotinib, a ARP(poly (ADP-ribose) polymerase) inhibitor, a CDK (cyclin-dependentkinase) inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4/6inhibitor, a HIF1α (hypoxia-inducible factor 1-α) inhibitor, a DNAligase inhibitor, a DNA ligase IV inhibitor, a NHEJ (non-homologous endjoining) inhibitor, a DNA ligase IV, a NHEJ inhibitor and a RAFinhibitor, a TKI and a RAF inhibitor, a TKI and RAF inhibitor such assorafenib, a PDT (photodynamic therapy) sensitizer, an ATR (ataxiatelangiectasia- and Rad3-related protein kinase) inhibitor, or acombination of any of the foregoing.

A compound comprising an IL-2Rα ligand or a pharmaceutical compositioncomprising a IL-2Rα ligand may be administered in conjunction with oneor more chemotherapeutic agents, such as, for example, a VEGFR inhibitorsuch as fruquintinib, motesanib/AMG-706, vatalanib; a RTK inhibitor suchas ponatinib; a sodium channel blocker such as GS967; a FAK inhibitorsuch as TAE226; a GLI1 and GLI2 inhibitor such as GANT61, a MEKinhibitor such as binimetinib; a RTA inhibitor such as linifanib; an ALKinhibitor such as brigstinib; bromopyruvic acid; a DNA alkylating agentsuch as thiotepa; nuclear translocations factors such as JSH-23; a PORCninhibitor such as Wnt-C59; a 5α-reductase inhibitor such as dutasteride;a topoisomerase inhibitor such as carubicin; a RAS inhibitor such asKobe0065; a CerK inhibitor such as NVP-231; an AKT inhibitor such asuprosertib; a EZH2 inhibitor such as GSK-503; a BET bromodomaininhibitor such as OTX015; a MEK5/ERK5 inhibitor such as BIX02189; aSyl/JAK inhibitor such as cerdulatinib; an IDO1 inhibitor such asNLG919; a retinoic X receptor activating agent such as bexsrotene; a PGPinhibitor such as acotiamide or actotiamide HCl; an Erk inhibitor suchSCH772984; a PI3K inhibitor such as gedatolisib; a JAK inhibitor such asruxolitinib; an AKT inhibitor such as afuresertib or afuresertib HCl; anALK1 inhibitor such as ceritinib; an HDAC inhibitor such as abexinostat;a DPP inhibitor such as oamarigliptin; an EGFR inhibitor such asgefittinib; an EZH2 inhibitor such as GSK126; a BTK inhibitor such asibrutinib; a kinase inhibitor such as imatinin HCl; an IDO inhibitorsuch as INCB024360; a DNA crosslinker such as mitomycin C; a tyrosinekinase inhibitor such as nilotinib, a PARP inhibitor such as olaparib; atubulin stabilization promoter such as paclitaxel; a CDK4/6 inhibitorsuch as palbociclib; a RTK inhibitor such as sunitinib; a PDT sensitizersuch as tslsporfin; a p-glycoprotein inhibitor such as tariquidar; anATR inhibitor such as VE-822; an HDAC inhibitor such as PCI-24781; a DPPinhibitor such as omarigliptin; an EGFR inhibitor such as gefinib; anEZH2 inhibitor such as GSK126; a BTK inhibitor such as irbrutinib; anIDO inhibitor such as INCB024360; or a combination of any of theforegoing.

An IL-2Rα binding compound provided by the present disclosure can beused as a vaccine adjuvant.

IL-2Rα binding compounds provided by the present disclosure can beuseful when combined with certain vaccines, including cancer neo-antigenvaccines. Mutations in tumor DNA produce new protein sequences that areforeign to the body. Vaccines can be designed to specifically activate apatient's immune system with respect to tumor-specific neoantigens. Whenadministered in combination with a neo-antigen vaccine, IL-2Rα bindingcompounds provided by the present disclosure can expand and proliferateneo-antigen-specific T-cells in the tumor microenvironment and therebydrive maximal expansion of vaccine-induced neoantigen-specific T-cellsfor the treatment of cancer.

IL-2Rα ligands and IL-2Rα constructs provided by the present disclosurecan be used as adjuvants. An adjuvant refers to a compound that enhancesthe efficacy of a vaccine without directly participating in theprotective immunity. For example, an IL-2Rα binding compound provided bythe present disclosure can be used in conjunction with a cancer vaccine.

IL-2Rα ligands and IL-2Rα ligand constructs provided by the presentdisclosure can be useful for cell therapy when engineered to beexpressed on the membrane surface of cells that also express the IL-2Rαsubunit. Adoptive immunotherapy using NK cells or using re-targetedchimeric antigen receptor (CAR) T-cells is currently being studied as atreatment for neoplasms and viral infections. One challenge with thesecell therapies is the suboptimal sustained survival of the infusedcells.

DNA encoding an IL-2Rα binding compound fused to a membrane protein insuch away that the IL-2Rα binding compound is expressed on theextracellular surface of a cell can be constructed using standardtechniques. When the fusion protein comprising the IL-2Rα bindingcompound is expressed, IL-7 receptors on the cell can become activatedleading to long-term persistence of the cell.

DNA encoding an IL-2Rα binding compound can be incorporated into a celland can be configured to produce an IL-2Rα binding compound provided bythe present disclosure. The IL-2Rα binding compound can be secreted fromthe cell and can interact with the secreting cells (i.e., autocrinesignaling) and/or cells in the vicinity of the secreting cell (i.e.,paracrine signaling). A secreted IL-2Rα binding compound provided by thepresent disclosure can be an IL-2R agonist and can be designed tolocalize near the secreting cell.

An IL-2Rα binding compound provided by the present disclosure can beused to expand non-regulatory T-cells within a patient or within abiological sample. Methods of increasing the ratio of non-regulatoryT-cells to Treg cells can comprise contacting a population of T-cellswith an effective amount of an IL-2Rα binding compound. The ratio can bemeasured by determining the ratio of CD3+FOXP3+ cells to CD3+FOXP3-cellswithin the population of T-cells. A typical Treg frequency in humanblood is 5% to 10% of the total CD4+CD3⁺ T-cells, however, in certaindiseases this percentage may be lower or higher.

An IL-2Rα binding compound can be used to expand NK cells. NK cellsmodified with chimeric antigen receptors (CARs), which redirect immunecell activity to target cancer cells have been demonstrated to exhibitimproved antitumor responses. CARs can comprise an antibody-derivedextracellular domain, which binds to the desired tumor-associatedantigen (TAA) and triggers an intracellular signaling cascade toactivate the immune cell against the target cells.

NK cells can be genetically engineered for enhanced expression of one ormore tumor targeting receptors such as NKG2D with membrane-bound IL-2Rαbinding compound, which can prolong the persistence and potency of theNK cells.

CAR T-cells can be genetically engineered to co-express a tethered formof an IL-2Rα binding compound provided by the present disclosure tosupport in vivo persistence and maintenance of an immature state ofdifferentiation and to exhibit in vivo antitumor activity.

IL-2Rα binding compounds provided by the present disclosure can also beutilized as commercial reagents for various medical research anddiagnostic uses. Such uses include, for example, (1) use as acalibration standard for quantitating the activities of candidate IL-2Ragonists in a variety of functional assays; (2) use to maintain theproliferation and growth of IL-7-dependent cell lines; (3) use instructural analysis of IL-2R through co-crystallization; (4) use toinvestigate the mechanism of IL-2R signal transduction/receptoractivation; and (5) other research and diagnostic applications whereIL-2R is activated or such activation is conveniently calibrated againsta known quantity of an IL-2R agonist.

Aspects of the present invention include nucleic acids encoding for anIL-2Rα binding compound provided by the present disclosure.

A nucleic acid or isolated polynucleotide encoding an IL-2Rα provided bythe present disclosure can be incorporated into expression vectorsdepending in part on the host cells used to produce the IL-2Rα bindingcompound. Generally, the nucleic acids can be operably linked to anynumber of regulatory elements such as, for example, promoters, origin ofreplication, selectable markers, ribosomal binding sites, and/orinducers. The expression vectors can be extra-chromosomal or integratingvectors.

The nucleic acids and/or expression can be transformed into any numberof different types of host cells including mammalian, bacterial, yeast,insect and/or fungal cells, with mammalian cells such as CHO cells.

A nucleic acid encoding an IL-2Rα binding compound can comprise a firstnucleic acid sequence encoding an IL-2Rα ligand; a second nucleic acidsequence encoding a peptidyl ligand linker; and a third nucleic acidsequence encoding an IL-2Rα ligand, an Rye ligand, and/or a constructpartner.

A nucleic acid encoding an IL-2Rα ligand fusion protein can comprise afirst nucleic acid sequence encoding the IL-2Rα ligand provided by thepresent disclosure; and a second nucleic acid sequence encoding a fusionpartner. A nucleic acid encoding an IL-2Rα ligand fusion protein cancomprise a nucleic acid encoding an IL-2Rα ligand and the fusionpartner. A nucleic acid encoding an IL-2Rα ligand fusion protein canfurther comprise a nucleic acid segment encoding a construct linker anda nucleic acid encoding an IL-2Rα ligand fusion protein can comprise anucleic acid encoding an IL-2Rα ligand, the fusion partner, and theconstruct linker.

The fusion partner can comprise, for example, HSA, an Fc-fragment, anIgG, an antibody directed to a cell-specific antigen, and an antibodydirected to a cell-specific receptor.

A nucleic acid encoding an IL-2Rα fusion protein can further comprise anucleic acid encoding a peptidyl linker, where the peptidyl linker isconfigured to bind the IL-2Rα ligand to the fusion partner.

A nucleic acid provided by the present disclosure can encode a fusionprotein comprising an IL-2Rα ligand, and a linker binding the C-terminusof the IL-2Rα ligand to HSA.

A nucleic acid provided by the present disclosure can encode a fusionprotein comprising a dimeric Fc-Fragment of IgG1, IgG2, or IgG4, anIL-2Rα ligand, and a linker binding the N-terminus of an IL-2Rα ligandto the C-terminus of one CH3 domain of the dimeric Fc-fragment.

A nucleic acid provided by the present disclosure can encode a fusionprotein comprising a dimeric Fc-Fragment of IgG1, IgG2, or IgG4, twoIL-2Rα ligands, and a linker binding the N-terminus of each of the twoIL-2Rα ligands to the C-terminus of each CH3 domain of the dimericFc-fragment.

A nucleic acid provided by the present disclosure can encode a fusionprotein comprising a heavy chain of an immunoglobulin molecule such asIgG1, IgG2, or IgG4, an IL-2Rα ligand, and a Fc linker bonding theN-terminus of the IL-2Rα ligand to the C-terminus of the Fc region.

A nucleic acid provided by the present disclosure can encode for anIL-2Rα ligand comprising an amino acid sequence of any one of SEQ IDNOS: 1-307 and 400-423, or can encode for an amino acid sequencecomprising an amino acid sequence having greater than 60%, greater than70%, greater than 80%, greater than 85%, greater than 90%, or greaterthan 95% sequence similarity to any one of SEQ ID NOS: 1-307 and400-423.

A nucleic acid provided by the present disclosure can encode for ahomomeric IL-2Rα ligand comprising two or more IL-2Rα ligands providedby the present disclosure.

Aspects of the invention further include a host cell comprising anexpression vector comprising a nucleic acid encoding an IL-2Rα ligand oran IL-2Rα binding compound provided by the present disclosure.

Methods provided by the present disclosure include methods of making anIL-2Rα ligand or an IL-2Rα binding compound provided by the presentdisclosure, comprising culturing a host cell, wherein the host cellcomprises an expression vector comprising a nucleic acid encoding anIL-2Rα ligand or an IL-2Rα binding compound provided by the presentdisclosure, under conditions where the IL-2Rα ligand or the IL-2Rαbinding compound is expressed, and recovering the expressed IL-2Rαligand or IL-2Rα binding compound.

EXAMPLES

The following examples describe in detail methods used for determiningthe activity of peptides comprising the IL-2Rα subunit. It will beapparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from the scopeof the disclosure.

Example 1 Phage Display pIII Library Panning Against Fc-Fusions onMagnetic Beads (Acid Elution) Library Panning Procedure

Fifty (50) μL of Protein G Dynabeads® (Invitrogen) was used for eachlibrary sample. After resuspending the stock bottle, the desired volumeof beads was transferred to a sterile microfuge tube and applied to themagnet.

With the beads on a magnet, the supernatant was removed, and the beadswere washed with 1 mL of PT buffer (1×PBS, 0.05% Tween®-20).

The supernatant was removed and 1 mL of PBS+1% BSA+0.05% Tween®-20 wasadded and mixed at 25° C. for at least 1 hour to block the beads.

A tube was applied to the magnet and the blocking solution was removed.For each library to be tested, 5 μg of a Fc-fused receptor of interestwas added to each library sample for each round to bring the totalvolume to at least 400 μL. The samples were mixed at 25° C. for at least1 h. The sample was applied to the magnet and the supernatant wasremoved.

Two-hundred 200 μL of PT buffer was added for each 50 μL of bead. Thesample was thoroughly mixed and 200 μL aliquots were transferred intotubes that were pre-labeled for each library to be screened. Anadditional 500 μL of PT was added to each tube, the samples mixed, andthen applied to the magnet. A total of 700 μL/tube was used for thewash.

The wash was removed and 500 μL of 250 nM Fc blocking peptide diluted inPBT (PBS+0.5% BSA+0.05% Tween®-20) was added to each sample. The stockconcentration was 25 μM (100×). The samples were incubated at 4° C. forat least 30 min while rotating. Following the incubation, the sampleswere applied to the magnet and the blocking peptide solution was removedprior to adding the libraries. One (1) mL aliquots of the librariesremoved from the −20° C. freezer. One-hundred (100 μL of 10×BT buffer(5% BSA, 0.5% Tween®-20 in 1×PBS) was added to each tube and vortexed.Eleven (11) μL of Fc blocking peptide was added to each library sampleand vortexed. The library samples were transferred to pre-labeled tubescontaining beads. The samples were then incubated at 4° C. on therotator for at least 2 h. For the additional rounds of screening, 1 mLaliquots of the amplification from the previous round from each librarywas used. Fc blocking peptide was then added at the concentrationindicated in step 6 (10 μL blocking peptide).

The beads were recovered with the magnet and the phage solution removed.The beads were washed 2× with 1 mL of PT buffer. Five-hundred (500) μLof PT buffer was added and the suspension was transferred to a cleantube. The beads were recovered on the magnet and the final wash removed.

Four-hundred seventy-five (475) μL of phage elution buffer was added toeach well (0.2 M glycine-HCL, pH 2.2, 1 mg/mL BSA). The samples wereincubated at 25° C. for 10 min on the rotator. The beads were recoveredon the magnet and the eluted phage transferred to a clean tube.

Twenty-five (25) μL of neutralization buffer (2M Tris Base) was added tothe 475 μL of elution. The neutralized samples were maintained at 4° C.until the TG1 cells were ready amplification. The samples were stored at−20° C. after screening. Fifty (50) L (about 10% of the total volume)was transferred to a 1.5 mL microfuge tube and store at −20° C. for usein deep sequencing.

Example 2 TG1 Culture and Library Amplification

Afresh TG1 (or OmniMax) culture was grown for about 1 to 1.5 h afteradding the libraries to the beads. 2X-YT medium (10 mL) was placed intoa 50 mL Falcon® tube. Two-hundred (200) μL of the TG1 overnight wasadded to the falcon tube. 2X-YT medium (600 μL) was placed in a cuvettefor OD600 blank. The culture was grown at 250 rpm and 37° C., taking thefirst OD measurement after 60 min. The TG1 cells should be in log phaseat the time of use with an OD600 of 0.5-0.7.

Eluted phage (400 μL to 450 μL) was added to 1 mL of the TG1 cells at anOD600 of 0.5-0.7 in a 50 mL Falcon® tube. The phage and TG1 cells wereincubated at 37° C. for 30 min without shaking. About 50 μL to 100 μLwas set aside for titering and characterization.

2YT medium (10.5 mL) was added to 12 μL of carbenicillin (carb) (100mg/mL to make 100 μg/mL) and 24 μL of 50% glucose (to make 0.1% glucose)and the cells incubated while shaking at 37° C. at 250 rpm for 1 h.

M13K07 helper phage (5×10¹⁰ pfu, 24 μL of the stock, 2×10² pfu/mL) wasthen added and swirled to mix. The phage and cells were incubated at 37°C. for 30 min without shaking.

Kanamycin was diluted to 3 mg/mL and arabinose to 2.4% in 2YTmedium/Carbenicillin-100/0.1% glucose and 100 μL was added to eachamplification. The mixture was incubated overnight at 37° C. and 250rpm.

The culture was transferred to a 50 mL high-speed VWR centrifuge tubeand centrifuged at 8,000 g for 15 min at 4° C. in a JSP-F50C centrifugeto pellet the cells.

The supernatant was transferred to a 50 mL high-speed VWR centrifugetube and 0.2 volumes of PEG/NaCl (multiply the volume by 0.25 mL to 3 mLPEG/NaCl for 12 mL amplification) was added, mixed, and incubated on icefor 30 minutes.

The cells were then centrifuged at 10,500 g for 15 min at 4° C. in aJSP-F50C centrifuge. The supernatant was removed, and the phage pelletwas resuspended in a total of 1 mL of PBT (1×PBS, 0.05% Tween® 20, 0.5%BSA) by pipetting.

The sample was transferred to an Eppendorf tube, vortexed, andcentrifuged at 12,000 rpm for 30 sec. The supernatant was transferred toa clean Eppendorf tube and stored at 4° C. This amplified phage sample(250-500 μL) was used for the next round of screening.

Example 3 Preparation of Cultures from Individual Colonies

Ninety-six (96) wells of a deep well plate were filled with 1 mL of 2YTbroth/Ampicillin-50/0.1% glucose. Ninety-six (96) colonies were placedinto the wells using P20 tips. The tips were left in the wells to markthe position. The tips were removed using a multi-channel pipette afterthe entire plate was completed. The plate was covered with a breathablefilm.

The inoculated plate(s) were incubated in a shaker at 37° C. until thecultures became turbid, typically within 4 h at 250 rpm.

The plate(s) was removed from the Incubator and 50 μL of the culturefrom each well was removed to another deep well block designated as the“Archive Block” containing 1 mL of 2YT broth/Ampicillin-50/0.1% glucose.The plate(s) were covered with a breathable film and incubated overnightat 37° C. and 250 rpm.

After incubating overnight, M13K07 helper phage was added to 2×10¹⁰pfu/mL in 2YT broth/Ampicillin-50/0.1% glucose (make 6.0 mL per block).Fifty (50) μL of the diluted M13K07 was added to each culture well inthe deep well block. The deep well block was covered with breathablefilm and incubated for 30 min at 37° C. and 250 rpm.

Kanamycin was diluted to 0.5 mg/ml and arabinose to 0.4% in 2YTbroth/Ampicillin-50/0.1% glucose (make 6.0 ml per block) and 50 μL wasadded to each well. The plate was covered with a breathable film andincubated overnight at 37° C. and 250 rpm.

The “Archive Block” culture was removed from the incubator and 50 μL wastransferred to a 96-well plate containing 50 μL of 50% glycerol. Theplate was sealed with foil and stored at −80° C. The remaining culturein the block was covered with a foil seal and stored at 4° C.

The block was centrifuged and inoculated with M13K07 at 4000 rpm for 15min. While avoiding the bacterial pellet, 850 μL of the phagesupernatant was transferred to a fresh deep well plate, covered with afoil seal, and stored at 4° C.

Example 4 ELISA Protocol for Fc-Fusions

For each block to be assayed, a 1×96 well ELISA plate was coated withFc-fusion (1 μg/mL in PBS) at 50 μL/well. The wells were incubated at25° C. for at least 1 h.

The Fc-fusion was removed from each well. Three-hundred (300) μL ofblocking buffer (1×PBS, 1% BSA) was added to each well of areceptor-coated plate. Also, 300 μL of the blocking buffer was added toa separate uncoated 96-well ELISA plate to be used as the negativecontrol. Both plates were covered with film and left at 37° C. for 1 hor overnight at 4° C.

The plate was washed 4 times with PT (1×PBS, 0.05% Tween® 20) buffer.

Fifty (50) μL of PBT was added to each well. Fifty (50) μL of the phagesupernatant from the block was added to each well and incubated at 4° C.for 1 h.

The plates were washed 4 times with cold PT.

To each well 100 μL of anti-M13-HRP antibody diluted 1:5000 in cold PBTwas added. The wells were incubated for 1 h at 4° C.

The plates were then washed 4 times with cold PT.

Fifty (50) μL of TMB was then added to each well, and the wells wereincubated for 1-10 min at 25° C. Fifty (50) μL of a “stop” solution wasadded and the plate read at 450 nm.

Example 5 Evaluation of Peptide Heteromer Ability to Activate IL-2Responsive Cells

Following the identification of peptidyl ligands that exhibit IL-2Rαbinding activity, compounds will be identified that exhibit IL-2Ragonist, IL-2R antagonist activity, and/or IL-2R binding activity. Thiscan involve assessing the ability of the peptide to polymerize theIL-2Rαβγc subunits and to signal in cell-based assays. Polymerization isa necessary, but not sufficient, step in the activation of IL-2 receptorsignaling. To assess agonist activity in cell-based assays, IL-2responsive cell lines will be tested for an indicator of IL-2 signaling,phosphorylation of STAT5. Compounds that exhibit IL-2R agonist activityin these cell lines will then be tested in primary human peripheralblood mononuclear cells (PBMC) for IL-2R agonism, and for the desiredselectivity favoring activation of cell types expressing IL-2Rβγcsubunits.

Polymerization potential will be assessed using a β-Gal complementationsystem in which a portion of the intracellular domains of eachrespective IL-2 receptor subunit is replaced with functionallycomplementary fragments of β-Gal, which regain catalytic activity whenbrought into sufficiently proximity. Cells expressing these constructsgenerate β-Gal activity, with an EC50 of about 26 nM, when treated withIL-2 (see DiscoverX product specifications). Candidate compounds will bescored for induction of STAT5 phosphorylation in two cell lines: (1)CTLL-2 cells, a mouse cytotoxic T-lymphocyte line that expresses allthree IL-2 receptor subunits, and which are responsive toIL-2Rβγc-biased variants as well as wild type IL-2; and (2) TF-1β cellsderived from the human erythroleukemia line TF-1, which naturallyexpress only IL-2Rγc, and are engineered to be IL-2 responsive bytransfection of IL-2Rβ. TF-1β will be constructed and IL-2R subunitexpression levels in both cell lines will be verified by QPCR and FACSanalysis.

Compounds will be tested in both cell lines. Dose response assays willbe conducted to determine EC50 of the test compounds and to compare thetest compounds with IL-2 as an indicator of IL-2Rβγc receptor bias. Tofurther characterize subunit bias, a parallel assay will be run in thepresence of a neutralizing antibody to the human IL-2Rβ subunit.

As a control to confirm that positive compounds are acting throughstimulation of the IL-2 receptor, the assay will also be done with cellstreated with neutralizing anti-huIL-2Rα antibody. To determine thatcompound activity is not due to contamination with cytokines, testcompounds will be treated with neutralizing antibodies (R&D Systems)against the natural IL-2Rβγc agonists, IL-2 and IL-15.

Compounds exhibiting IL-2R agonist activity in the cell lines will betested on human primary immune cells, PBMCs, collected from individualdonors (commercially available from Lonza and others), and in some caseson purified CD4+CD8+ cells (Lonza). A substantial fraction of PBMCs fromnormal donors are responsive to IL-2. To assess IL-2 agonist activity ofthe test compounds, cells will be exposed to the compounds or IL-2 andscored for STAT5 phosphorylation by western blot analysis. As a controlto confirm that positive compounds are acting through direct stimulationof the IL-2 receptor, the assay will also be done with cells treatedwith neutralizing anti-huRα antibody.

Those compounds exhibiting STAT5 activation of PBMCs will be subjectedto a follow-on assay designed to assess subunit bias of the compoundscompared to IL-2. This assay will involve determining a dose response ofthe test compounds and IL-2 (1 to 1000 I) over 30 min, scored by aFACS-based protocol allowing detection of both intracellular pSTAT5 asan indicator of IL-2R activation, and cell surface CD25, the IL-2Rβsubunit. Cells expressing the three IL-2R subunits, IL-2Rαβγc, bind IL-2with very high affinity (about 10 μM) and are therefore sensitive to lowconcentrations of IL-2; whereas cells expressing only IL-2Rβγc (about 1nM affinity) require exposure to substantially higher IL-2 levels foractivation. Because compounds provided by the present disclosure areselected for binding to the IL-2Rα the potency of the compoundscomprising an IL-2Rα ligand is expected to be correlated with the levelof expression of IL-2Rα on cells; and comparison of response profiles ofcells treated with compounds provided by the present disclosure ortreated with IL-2 should reveal any bias.

Example 6 Identified Peptides

Stochastic libraries with each library containing approximately 10billion independent recombinants, with each clone potentially displayinga unique peptide sequence have been screened for binding to the humanIL-2Rα subunit. In screening these initial libraries against the IL-2Rαsubunit extracellular domain (ECD), unique peptide clones wereidentified and confirmed as ligands of IL-2Rα. These IL-2Rα ligands canbe grouped into sequence families that exhibit a clear consensussequence.

Example 7 Chemical Synthesis of IL-2Rα.Ligands

2—Cholorotrityl resin (1 g, 1.5 mmole/g, from Anaspec) was washed withDMF (2×), and then allowed to stand in 50 mL DMF for 10 min. The swollenresin was treated with an activated solution of Fmoc-glycine preparedfrom 5 eq. of amino acid and 5 eq. of HATU dissolved at 0.5M in DMF,followed by the addition of 10 eq. of DIEA, and the mixture gentlystirred for 30 min at 25° C. The resin was washed (DMF, THF, DCM, andMeOH) and dried to yield the Fmoc-protected resin. Fmoc groups were thenremoved by gently shaking the resin with 30% piperidine in DMF for 20min, followed by washing (DMF, THF, DCM, and MeOH), and drying. Theresin was then subjected to repeated cycles of Fmoc-amino acid couplingswith HATU activation and Fmoc removal with piperidine to build a desiredamino acid sequence. Except for examples with four cysteine residues inthe sequence, standard 95% TFA-labile amino acid side chain protectinggroups were used. With compounds with four cysteines, the two cysteineresidues proximal to the resin, Trt protection was used, and for the twocysteine residues distal to the resin, Acm protection was used. AfterFmoc removal from the final amino acid of the dimer sequence, in somecases the terminal amine groups were acylated with acetic anhydride (10eq.) and DIEA (20 eq.) in DMF for 20 min, followed by washing asdescribed above.

The completed peptide was cleaved from the resin by suspension in asolution of TFA (95 vol %), water (2.5 vol %), and triisopropylsilane(2.5 vol %) for 3 h at 25° C. The TFA solution was cooled to 5° C. andpoured into Et₂O to precipitate the peptide. Filtration and drying underreduced pressure gave the desired peptide. Purification via preparativeHPLC with a C18 column afforded the pure peptide with the two C-terminalthiol groups in a reduced state. This peptide was dissolved in 20%DMSO/water (1 mg dry weight peptide/mL) and allowed to stand at 25° C.for 36 h, and then purified by reverse phase HPLC to provide the peptidewith the two C-terminal thiols linked by a disulfide bridge. Incompounds containing four cysteines, the two N-terminal Acm-protectedcysteine residues were then deprotected by dissolving 0.1 mmole ofpeptide in 25 mL of 50% acetic acid/H₂O and 2.5 mL of 1M HCl and adding5 mL of 0.1M iodine (in glacial acetic acid; 5 eq.) dropwise withstirring under a nitrogen atmosphere. The deprotection/oxidationreaction was allowed to proceed for 2 h at 25° C. with frequentmonitoring (analytical HPLC) to ensure complete reaction. The reactionwas stopped by addition of ice-cooled diethyl ether (9 volume eq.). Theresulting solution was cooled on dry ice (3 min), the ether solutioncarefully decanted, and the resulting light-yellow solid purified bypreparative reverse phase HPLC (95%) to yield the final IL-2Rα ligand orpeptide having an IL-2Rα ligand.

IL-2Rα ligands having SEQ ID NO: 400 to SEQ ID NO: 423 were synthesized.

ASPECTS OF THE INVENTION

The invention is further defined by the following aspects.

Aspect 1. An IL-2Rα ligand, wherein the IL-2Rα ligand binds to the humanIL-2Rα subunit with an IC₅₀ of less than 100 μM.

Aspect 2. The IL-2Rα ligand of aspect 1, wherein the IL-2Rα ligandcomprises from 5 to 30 amino acids.

Aspect 3. The IL-2Rα ligand of any one of aspects 1 to 2, wherein theIL-2Rα ligand binds to the human IL-2Rα subunit with an IC₅₀ from 1 μMto 100 μM.

Aspect 4. The IL-2Rα ligand of any one of aspects 1 to 2, wherein theIL-2Rα ligand binds to the human IL-2Rα subunit with an IC₅₀ from 0.1 μMto 50 μM.

Aspect 5. The IL-2Rα ligand of any one of aspects 1 to 2, wherein theIL-2Rα ligand binds to the human IL-2Rα subunit with an IC₅₀ of lessthan 100 μM.

Aspect 6. The IL-2Rα ligand of any one of aspects 1 to 2, wherein theIL-2Rα ligand binds to a mammalian IL-2Rα subunit with an IC₅₀ of lessthan 100 μM.

Aspect 7. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (1) (SEQ IDNO: 1):

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (1)

wherein,

-   -   X¹ is selected from an amino acid comprising a large hydrophobic        side chain or an aromatic side chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid;    -   X⁴ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁵ is selected from an amino acid comprising a small hydrophobic        side chain or a polar/neutral side chain;    -   X⁶ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁷ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁸ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid comprising a polar/neutral        side chain;    -   X¹¹ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 8. The IL-2Rα ligand of aspect 7, wherein X¹ is selected from F,H, I, L, M, V, W, and Y.

Aspect 9. The IL-2Rα ligand of any one of aspects 7 to 8, wherein X² isselected from F, I, L, M, V, W, and Y.

Aspect 10. The IL-2Rα ligand of any one of aspects 7 to 9, wherein X³ isselected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, andY.

Aspect 11. The IL-2Rα ligand of any one of aspects 7 to 10, wherein X⁴is selected from F, I, L, M, V, W, and Y.

Aspect 12. The IL-2Rα ligand of any one of aspects 7 to 11, wherein X⁵is selected from H, N, Q, Y, A, G, P, S, and T.

Aspect 13. The IL-2Rα ligand of any one of aspects 7 to 12, wherein X⁶is selected from F, I, L, M, V, W, and Y.

Aspect 14. The IL-2Rα ligand of any one of aspects 7 to 13, wherein X⁷is selected from F, I, L, M, V, W, and Y.

Aspect 15. The IL-2Rα ligand of any one of aspects 7 to 14, wherein X⁸is selected from F, I, L, M, V, W, and Y.

Aspect 16. The IL-2Rα ligand of any one of aspects 7 to 15, wherein X⁹is selected from A, G, P, S, and T.

Aspect 17. The IL-2Rα ligand of any one of aspects 7 to 16, wherein X¹⁰is selected from H, N, Q, S, T, and Y.

Aspect 18. The IL-2Rα ligand of any one of aspects 7 to 177, wherein X¹¹is selected from F, I, L, M, V, W, and Y.

Aspect 19. The IL-2Rα ligand of any one of aspects 7 to 18, wherein X¹²is selected from F, I, L, M, V, W, and Y.

Aspect 20. The IL-2Rα ligand of any one of aspects 7 to 19, wherein X¹is selected from L, W, and F.

Aspect 21. The IL-2Rα ligand of any one of aspects 7 to 20, wherein X²is selected from D, A, L, and V.

Aspect 22. The IL-2Rα ligand of any one of aspects 7 to 21, wherein X³is selected from L, V, H, P, and E.

Aspect 23. The IL-2Rα ligand of any one of aspects 7 to 22, wherein X⁴is selected from T, D, and W.

Aspect 24. The IL-2Rα ligand of any one of aspects 7 to 23, wherein X⁵is selected from Y, W, P, and Q.

Aspect 25. The IL-2Rα ligand of any one of aspects 7 to 24, wherein X⁶is selected from D, S, V, and A.

Aspect 26. The IL-2Rα ligand of any one of aspects 7 to 25, wherein X⁷is selected from E and Y.

Aspect 27. The IL-2Rα ligand of any one of aspects 7 to 26, wherein X⁸is selected from L and F.

Aspect 28. The IL-2Rα ligand of any one of aspects 7 to 27, wherein X⁹is selected from L, R, and S.

Aspect 29. The IL-2Rα ligand of any one of aspects 7 to 28, wherein X¹⁰is selected from A, R, and Q.

Aspect 30. The IL-2Rα ligand of any one of aspects 7 to 29, wherein X¹¹is selected from C, R, V, and M.

Aspect 31. The IL-2Rα ligand of any one of aspects 7 to 30, wherein X¹²is selected from T, L, and M.

Aspect 32. The IL-2Rα ligand of any one of aspects 7 to 31, wherein X¹is F.

Aspect 33. The IL-2Rα ligand of any one of aspects 7 to 32, wherein X²is selected from L and V.

Aspect 34. The IL-2Rα ligand of any one of aspects 7 to 33, wherein X³is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 35. The IL-2Rα ligand of any one of aspects 7 to 34, wherein X⁴is W.

Aspect 36. The IL-2Rα ligand of any one of aspects 7 to 35, wherein X⁵is P.

Aspect 37. The IL-2Rα ligand of any one of aspects 7 to 36, wherein X⁶is V.

Aspect 38. The IL-2Rα ligand of any one of aspects 7 to 37, wherein X⁷is Y.

Aspect 39. The IL-2Rα ligand of any one of aspects 7 to 38, wherein X⁸is F.

Aspect 40. The IL-2Rα ligand of any one of aspects 7 to 39, wherein X⁹is S.

Aspect 41. The IL-2Rα ligand of any one of aspects 7 to 40, wherein X¹⁰is Q.

Aspect 42. The IL-2Rα ligand of any one of aspects 7 to 41, wherein X¹¹is selected from N and V.

Aspect 43. The IL-2Rα ligand of any one of aspects 7 to 42, wherein X¹²is selected from L and M.

Aspect 44. The IL-2Rα ligand of aspect 7, wherein X¹ is F, X⁴ is W, X⁵is P, X⁶, is V, X⁷ is Y, X⁸ is F, X⁹ is S, and X¹⁰ is Q.

Aspect 45. The IL-2Rα ligand of aspect 7,

X¹ is F;

X² is selected from F, H, I, L, M, V, W, and Y;

X³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁴ is W;

X⁵ is selected from H, N, Q, Y, A, G, P, S, and T;

X⁶ is V;

X⁷ is Y;

X⁸ is F;

X⁹ is S;

X¹⁰ is Q;

X¹¹ is selected from F, I, L, M, V, W, and Y; and

X¹² is selected from F, I, L, M, V, W, and Y.

Aspect 46. The IL-2Rα ligand of aspect 7, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 2to SEQ ID NO: 6:

SEQ ID NO: 2 L D L T Y D E L L A C T SEQ ID NO: 3 W A Y D W S C F R R RL SEQ ID NO: 4 F L H W P V Y F C Q V M SEQ ID NO: 5 F L P W P V Y F S QV L SEQ ID NO: 6 F V E W Q A Y F S Q M M

Aspect 47. The IL-2Rα ligand of any one of aspects 7 to 46, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 48. The IL-2Rα ligand of aspects 46 to 47, wherein from 1 to 5 ofthe amino acids is independently substituted with another amino acid.

Aspect 49. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (2) (SEQ IDNO: 7):

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (2)

wherein,

-   -   X¹ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁴ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁵ is selected from an amino acid comprising an acidic side        chain;    -   X⁶ is selected from an amino acid comprising an acidic side        chain;    -   X⁷ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁸ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁹ is selected from an amino acid;    -   X¹⁰ is selected from an amino acid comprising a polar/neutral        side chain;    -   X¹¹ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 50. The IL-2Rα ligand of aspect 49, wherein X¹ is selected fromF, I, L, M, V, W, and Y.

Aspect 51. The IL-2Rα ligand of any one of aspects 49 to 50, wherein X²is selected from F, I, L, M, V, W, and Y.

Aspect 52. The IL-2Rα ligand of any one of aspects 49 to 51, wherein X³is selected from A, G, P, S, and T.

Aspect 53. The IL-2Rα ligand of any one of aspects 49 to 52, wherein X⁴is selected from F, I, L, M, V, W, and Y.

Aspect 54. The IL-2Rα ligand of any one of aspects 49 to 53, wherein X⁶is selected from D and E.

Aspect 55. The IL-2Rα ligand of any one of aspects 49 to 54, wherein X⁷is selected from F, I, L, M, V, W, and Y.

Aspect 56. The IL-2Rα ligand of any one of aspects 49 to 55, wherein X⁸is selected from F, I, L, M, V, W, and Y.

Aspect 57. The IL-2Rα ligand of any one of aspects 49 to 56, wherein X⁹is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 58. The IL-2Rα ligand of any one of aspects 49 to 57, wherein X¹⁰is selected from H, N, Q, S, T, and Y.

Aspect 59. The IL-2Rα ligand of any one of aspects 49 to 58, wherein X¹¹is selected from F, I, L, M, V, W, and Y.

Aspect 60. The IL-2Rα ligand of any one of aspects 49 to 59, wherein X¹²is selected from F, I, L, M, V, W, and Y.

Aspect 61. The IL-2Rα ligand of any one of aspects 49 to 60, wherein X¹is F.

Aspect 62. The IL-2Rα ligand of any one of aspects 49 to 61, wherein X²is selected from I, L, and V.

Aspect 63. The IL-2Rα ligand of any one of aspects 49 to 62, wherein X³is P.

Aspect 64. The IL-2Rα ligand of any one of aspects 49 to 63, wherein X⁴is W.

Aspect 65. The IL-2Rα ligand of any one of aspects 49 to 64, wherein X⁵is selected from P, D, and E.

Aspect 66. The IL-2Rα ligand of any one of aspects 49 to 65, wherein X⁶is selected from V and E.

Aspect 67. The IL-2Rα ligand of any one of aspects 49 to 66, wherein X⁷is Y.

Aspect 68. The IL-2Rα ligand of any one of aspects 49 to 67, wherein X⁸is F.

Aspect 69. The IL-2Rα ligand of any one of aspects 49 to 68, wherein X⁹is selected from S, A, K, and L.

Aspect 70. The IL-2Rα ligand of any one of aspects 49 to 69, wherein X¹⁰is Q.

Aspect 71. The IL-2Rα ligand of any one of aspects 49 to 70, wherein X¹¹is selected from V, I, and L.

Aspect 72. The IL-2Rα ligand of any one of aspects 49 to 71, wherein X¹²is selected from L and M.

Aspect 73. The IL-2Rα ligand of any one of aspects 49 to 72, wherein X¹is F.

Aspect 74. The IL-2Rα ligand of any one of aspects 49 to 73, wherein X²is selected from L and V.

Aspect 75. The IL-2Rα ligand of any one of aspects 49 to 74, wherein X³is P.

Aspect 76. The IL-2Rα ligand of any one of aspects 49 to 75, wherein X⁴is W.

Aspect 77. The IL-2Rα ligand of any one of aspects 49 to 76, wherein X⁵is D.

Aspect 78. The IL-2Rα ligand of any one of aspects 49 to 77, wherein X⁶is E.

Aspect 79. The IL-2Rα ligand of any one of aspects 49 to 78, wherein X⁷is Y.

Aspect 80. The IL-2Rα ligand of any one of aspects 49 to 79, wherein X⁸is F.

Aspect 81. The IL-2Rα ligand of any one of aspects 49 to 80, wherein X⁹is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 82. The IL-2Rα ligand of any one of aspects 49 to 80, wherein X⁹is S.

Aspect 83. The IL-2Rα ligand of any one of aspects 49 to 82, wherein X¹⁰is Q.

Aspect 84. The IL-2Rα ligand of any one of aspects 49 to 83, wherein X¹¹is selected from I, L, and V.

Aspect 85. The IL-2Rα ligand of any one of aspects 49 to 84, wherein X¹²is L.

Aspect 86. The IL-2Rα ligand of aspect 49, wherein X¹ is F, X³ is P, X⁴is W, X⁵ is D,

X⁶, is E, X⁷ is Y, X⁸ is F, X¹⁰ is Q, and X¹² is L.

Aspect 87. The IL-2Rα ligand of aspect 49, wherein,

X¹ is F;

X² is selected from F, I, L, M, V, W, and Y;

X³ is P;

X⁴ is W;

X⁵ is selected from D and P;

X⁶ is E;

X⁷ is Y;

X⁸ is F;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is Q;

X¹¹ is selected from F, I, L, M, V, W, and Y; and

X¹² is L.

Aspect 88. The IL-2Rα ligand of aspect 49, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 8to SEQ ID NO: 15:

SEQ ID NO: 8 F I P W D E Y F A Q L L SEQ ID NO: 9 F I P W D E Y F K Q VL SEQ ID NO: 10 F V P W D V Y F S Q I L SEQ ID NO: 11 F I P W D E Y F KQ V L SEQ ID NO: 12 F V P W P E Y F L Q I M SEQ ID NO: 13 F I P W E E YF S Q L L SEQ ID NO: 14 F I P W P E Y F S Q L L SEQ ID NO: 15 F V P W DE Y F L Q I L

Aspect 89. The IL-2Rα ligand of any one of aspects 49 to 88, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 90. The IL-2Rα ligand of any one of aspects 88 to 89, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 91. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (3a) (SEQ IDNO: 16), the amino acid sequence of Formula (3b) (SEQ ID NO: 17), or theamino acid sequence of Formula (3c) (SEQ ID NO: 18):

—X⁵—X⁶—X⁷—X⁸—  (3a)

—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—  (3b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (3c)

wherein,

-   -   X¹ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from amino acid comprising a small hydrophobic        side chain;    -   X⁹ is C;    -   X¹⁰ is selected from an amino acid comprising a basic side chain        or a polar/neutral side chain;    -   X¹¹ is selected from an amino acid comprising a small        hydrophobic side chain; and    -   X¹² is selected from an amino acid.

Aspect 92. The IL-2Rα ligand of aspect 91, wherein X¹ is selected fromF, I, L, M, V, W, and Y.

Aspect 93. The IL-2Rα ligand of any one of aspects 91 to 92, wherein X²is selected from F, I, L, M, V, W, and Y.

Aspect 94. The IL-2Rα ligand of any one of aspects 91 to 93, wherein X³is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 95. The IL-2Rα ligand of any one of aspects 91 to 94, wherein X⁴is C.

Aspect 96. The IL-2Rα ligand of any one of aspects 91 to 95, wherein X⁵is selected from A, G, P, S, and T.

Aspect 97. The IL-2Rα ligand of any one of aspects 91 to 96, wherein X⁶is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 98. The IL-2Rα ligand of any one of aspects 91 to 97, wherein X⁷is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y.

Aspect 99. The IL-2Rα ligand of any one of aspects 91 to 98, wherein X⁸is selected from A, G, P, S, and T.

Aspect 100. The IL-2Rα ligand of any one of aspects 91 to 99, wherein X⁹is C.

Aspect 101. The IL-2Rα ligand of any one of aspects 91 to 100, whereinX¹⁰ is selected from H, K, N, Q, R, S, T, and Y.

Aspect 102. The IL-2Rα ligand of any one of aspects 91 to 101, whereinX¹¹ is selected from A, G, P, S, and T.

Aspect 103. The IL-2Rα ligand of any one of aspects 91 to 102, whereinX¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 104. The IL-2Rα ligand of any one of aspects 91 to 103, whereinX¹ is selected from Y and W.

Aspect 105. The IL-2Rα ligand of any one of aspects 91 to 104, whereinX² is V.

Aspect 106. The IL-2Rα ligand of any one of aspects 91 to 105, whereinX³ is selected from M and I.

Aspect 107. The IL-2Rα ligand of any one of aspects 91 to 106, whereinX⁴ is C.

Aspect 108. The IL-2Rα ligand of any one of aspects 91 to 107, whereinX⁵ is S.

Aspect 109. The IL-2Rα ligand of any one of aspects 91 to 108, whereinX⁶ is A.

Aspect 110. The IL-2Rα ligand of any one of aspects 91 to 109, whereinX⁷ is F, L, V, and M.

Aspect 111. The IL-2Rα ligand of any one of aspects 91 to 110, whereinX⁸ is G.

Aspect 112. The IL-2Rα ligand of any one of aspects 91 to 111, whereinX⁹ is C.

Aspect 113. The IL-2Rα ligand of any one of aspects 91 to 112, whereinX¹⁰ is selected from K and R.

Aspect 114. The IL-2Rα ligand of any one of aspects 91 to 113, whereinX¹¹ is selected from S, P, and A.

Aspect 115. The IL-2Rα ligand of any one of aspects 91 to 114, whereinX¹² is selected from I, L, M, F, and W.

Aspect 116. The IL-2Rα ligand of any one of aspects 91 to 115, whereinX¹ is selected from F, I, L, M, V, W, and Y.

Aspect 117. The IL-2Rα ligand of any one of aspects 91 to 116, whereinX² is V.

Aspect 118. The IL-2Rα ligand of any one of aspects 91 to 117, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 119. The IL-2Rα ligand of any one of aspects 91 to 118, whereinX⁴ is C.

Aspect 120. The IL-2Rα ligand of any one of aspects 91 to 119, whereinX⁵ is G.

Aspect 121. The IL-2Rα ligand of any one of aspects 91 to 120, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 122. The IL-2Rα ligand of any one of aspects 91 to 121, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 123. The IL-2Rα ligand of any one of aspects 91 to 122, whereinX⁸ is G.

Aspect 124. The IL-2Rα ligand of any one of aspects 91 to 123, whereinX⁹ is C.

Aspect 125. The IL-2Rα ligand of any one of aspects 91 to 124, whereinX¹⁰ is R.

Aspect 126. The IL-2Rα ligand of any one of aspects 91 to 125, whereinX¹¹ is S.

Aspect 127. The IL-2Rα ligand of any one of aspects 91 to 126, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 128. The IL-2Rα ligand of any one of aspects 91 to 126, whereinX¹² is V.

Aspect 129. The IL-2Rα ligand of aspect 91, wherein X² is V, X⁴ is C, X⁵is G, X⁸ is G,

X⁹ is C, X¹⁰ is R, and X¹¹ is S.

Aspect 130. The IL-2Rα ligand of aspect 91, wherein,

X¹ is selected from F, I, L, M, V, W, and Y;

X² is V;

X³ is selected from F, I, L, M, V, W, and Y;

X⁴ is C;

X⁵ is G;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is G;

X⁹ is C;

X¹⁰ is R;

X¹¹ is S; and

X¹² is selected from F, I, L, M, V, W, and Y.

Aspect 131. The IL-2Rα ligand of aspect 91, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 19to SEQ ID NO: 24:

SEQ ID NO: 19 F V L C G L Q G C R G S SEQ ID NO: 20 K V I C G W D G C RSEQ ID NO: 21 L V F C G K N G C H S G SEQ ID NO: 22 V V L C T P K G C RS A SEQ ID NO: 23 Y V M C S A F G C K S I SEQ ID NO: 24 F V H C T L L GC W S G

Aspect 132. The IL-2Rα ligand of any one of aspects 91 to 131, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 133. The IL-2Rα ligand of any one of aspects 131 to 132, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 134. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (4a) (SEQ IDNO: 25), the amino acid sequence of Formula (4b) (SEQ ID NO: 26), theamino acid sequence of Formula (4c) (SEQ ID NO: 27), or the amino acidsequence of Formula (4d) (SEQ ID NO: 28):

—X⁵—X⁶—X⁷—X⁸—X⁹—  (4a)

—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—  (4b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—C—X¹⁰—X¹¹—  (4c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (4d)

wherein,

-   -   X¹ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁷ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁸ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁹ is C;    -   X¹⁰ is selected from an amino acid comprising a basic side        chain;    -   X¹¹ is selected from an amino acid comprising a small        hydrophobic side chain; and    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 135. The IL-2Rα ligand of aspect 134, wherein X¹ is selected fromF, I, L, M, V, W, and Y.

Aspect 136. The IL-2Rα ligand of any one of aspects 134 to 135, whereinX² is selected from F, I, L, M, V, W, and Y.

Aspect 137. The IL-2Rα ligand of any one of aspects 134 to 136, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 138. The IL-2Rα ligand of any one of aspects 134 to 137, whereinX⁴ is C.

Aspect 139. The IL-2Rα ligand of any one of aspects 134 to 138, whereinX⁵ is selected from A, G, P, S, and T.

Aspect 140. The IL-2Rα ligand of any one of aspects 134 to 139, whereinX⁶ is selected from A, G, P, S, and T.

Aspect 141. The IL-2Rα ligand of any one of aspects 134 to 140, whereinX⁷ is selected from F, I, L, M, V, W, and Y.

Aspect 142. The IL-2Rα ligand of any one of aspects 134 to 141, whereinX⁸ is selected from A, G, P, S, and T.

Aspect 143. The IL-2Rα ligand of any one of aspects 134 to 142, whereinX⁹ is C.

Aspect 144. The IL-2Rα ligand of any one of aspects 134 to 143, whereinX¹⁰ is selected from H, K, and R.

Aspect 145. The IL-2Rα ligand of any one of aspects 134 to 144, whereinX¹¹ is selected from A, G, P, S, and T.

Aspect 146. The IL-2Rα ligand of any one of aspects 134 to 145, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 147. The IL-2Rα ligand of any one of aspects 134 to 146, whereinX¹ is selected from Y and W.

Aspect 148. The IL-2Rα ligand of any one of aspects 134 to 147, whereinX² is V.

Aspect 149. The IL-2Rα ligand of any one of aspects 134 to 148, whereinX³ is selected from M and I.

Aspect 150. The IL-2Rα ligand of any one of aspects 134 to 149, whereinX⁴ is C.

Aspect 151. The IL-2Rα ligand of any one of aspects 134 to 150, whereinX⁵ is S.

Aspect 152. The IL-2Rα ligand of any one of aspects 134 to 151, whereinX⁶ is A.

Aspect 153. The IL-2Rα ligand of any one of aspects 134 to 152, whereinX⁷ is selected from F, L, V, and M.

Aspect 154. The IL-2Rα ligand of any one of aspects 134 to 153, whereinX⁸ is G.

Aspect 155. The IL-2Rα ligand of any one of aspects 134 to 154, whereinX⁹ is C.

Aspect 156. The IL-2Rα ligand of any one of aspects 134 to 155, whereinX¹⁰ is selected from R and K.

Aspect 157. The IL-2Rα ligand of any one of aspects 134 to 156, whereinX¹¹ is selected from S, P, and A.

Aspect 158. The IL-2Rα ligand of any one of aspects 134 to 157, whereinX¹² is selected from I, M, F, and W.

Aspect 159. The IL-2Rα ligand of any one of aspects 134 to 158, whereinX¹ is W.

Aspect 160. The IL-2Rα ligand of any one of aspects 134 to 159, whereinX² is V.

Aspect 161. The IL-2Rα ligand of any one of aspects 134 to 160, whereinX³ is I.

Aspect 162. The IL-2Rα ligand of any one of aspects 134 to 161, whereinX⁴ is C.

Aspect 163. The IL-2Rα ligand of any one of aspects 134 to 162, whereinX⁵ is S

Aspect 164. The IL-2Rα ligand of any one of aspects 134 to 163, whereinX⁶ is A.

Aspect 165. The IL-2Rα ligand of any one of aspects 134 to 164, whereinX⁷ is selected from F, I, L, M, V, W, and Y.

Aspect 166. The IL-2Rα ligand of any one of aspects 134 to 165, whereinX⁸ is G.

Aspect 167. The IL-2Rα ligand of any one of aspects 134 to 166, whereinX⁹ is C.

Aspect 168. The IL-2Rα ligand of any one of aspects 134 to 167, whereinX¹⁰ is R.

Aspect 169. The IL-2Rα ligand of any one of aspects 134 to 168, whereinX¹¹ is S.

Aspect 170. The IL-2Rα ligand of any one of aspects 134 to 169, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 171. The IL-2Rα ligand of aspect 134, wherein X¹ is W, X² is V,X³ is I, X⁴ is C,

X⁵ is S, X⁶ is A, X⁸ is G, X⁹ is C, X¹⁰ is R, and X¹¹ is S.

Aspect 172. The IL-2Rα ligand of aspect 134, wherein,

X¹ is W;

X² is V;

X³ is I;

X⁴ is C;

X⁵ is S;

X⁶ is A;

X⁷ is selected from F, I, L, M, V, W, and Y.

X⁸ is G;

X⁹ is C;

X¹⁰ is selected from R and K;

X¹¹ is S; and

X¹² is selected from F, I, L, M, V, W, and Y.

Aspect 173. The IL-2Rα ligand of aspect 134, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 29to SEQ ID NO: 36:

SEQ ID NO: 29 W V I C S A L G C R S L SEQ ID NO: 30 W V I C S A L G C RS M SEQ ID NO: 31 W V I C S A V G C R P F SEQ ID NO: 32 W V I C S A M GC R S I SEQ ID NO: 33 W V I C S A L G C R S I SEQ ID NO: 34 W V I C S AF G C R S M SEQ ID NO: 35 W V I C S A L G C R P F SEQ ID NO: 36 W V I CS A L G C K A W

Aspect 174. The IL-2Rα ligand of any one of aspects 134 to 173, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 175. The IL-2Rα ligand of any one of aspects 173 to 174, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 176. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (5a) (SEQ IDNO: 37), the amino acid sequence of Formula (5b) (SEQ ID NO: 38), theamino acid sequence of Formula (5c) (SEQ ID NO: 39), or the amino acidsequence of Formula (5d) (SEQ ID NO: 40):

—X⁵—X⁶—X⁷—X⁸—X⁹—  (5a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—C—X¹¹—  (5b)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—C—X¹¹—X¹²—  (5c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (5d)

wherein,

-   -   X¹ is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a small hydrophobic        side chain or an acidic side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is C;    -   X¹¹ is selected from an amino acid comprising a basic side        chain; and    -   X¹² is selected from an amino acid.

Aspect 177. The IL-2Rα ligand of aspect 176, wherein X¹ is selected fromF, H, I, L, M, V, W, and Y.

Aspect 178. The IL-2Rα ligand of any one of aspects 176 to 177, whereinX² is selected from F, I, L, M, V, W, and Y.

Aspect 179. The IL-2Rα ligand of any one of aspects 176 to 178, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 180. The IL-2Rα ligand of any one of aspects 176 to 179, whereinX⁴ is C.

Aspect 181. The IL-2Rα ligand of any one of aspects 176 to 180, whereinX⁵ is selected from A, G, H, K, P, R, S, and T.

Aspect 182. The IL-2Rα ligand of any one of aspects 176 to 181, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 183. The IL-2Rα ligand of any one of aspects 176 to 182, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 184. The IL-2Rα ligand of any one of aspects 176 to 183, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 185. The IL-2Rα ligand of any one of aspects 176 to 184, whereinX⁹ is selected from A, G, P, S, and T.

Aspect 186. The IL-2Rα ligand of any one of aspects 176 to 185, whereinX¹⁰ is C.

Aspect 187. The IL-2Rα ligand of any one of aspects 176 to 186, whereinX¹¹ is selected from H, K, and R.

Aspect 188. The IL-2Rα ligand of any one of aspects 176 to 187, whereinX¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 189. The IL-2Rα ligand of any one of aspects 176 to 188, whereinX¹ is selected from F, H, W, and Y.

Aspect 190. The IL-2Rα ligand of any one of aspects 176 to 189, whereinX² is V.

Aspect 191. The IL-2Rα ligand of any one of aspects 176 to 190, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 192. The IL-2Rα ligand of any one of aspects 176 to 191, whereinX⁴ is selected from F, K, L, V, W, and H.

Aspect 193. The IL-2Rα ligand of any one of aspects 176 to 192, whereinX⁵ is V.

Aspect 194. The IL-2Rα ligand of any one of aspects 176 to 193, whereinX⁵ is selected from L, F, M, H, T, A, and I.

Aspect 195. The IL-2Rα ligand of any one of aspects 176 to 194, whereinX⁵ is C.

Aspect 196. The IL-2Rα ligand of any one of aspects 176 to 195, whereinX⁶ is selected from G, T, S, R, and K.

Aspect 197. The IL-2Rα ligand of any one of aspects 176 to 196, whereinX⁶ is selected from L, W, K, P, A, N, W, and V.

Aspect 198. The IL-2Rα ligand of any one of aspects 176 to 197, whereinX⁷ is selected from Q, D, N, K, F, L, R, G, and D,

Aspect 199. The IL-2Rα ligand of any one of aspects 176 to 198, whereinX⁸ is selected from G, N, Y, H, and G.

Aspect 200. The IL-2Rα ligand of any one of aspects 176 to 199, whereinX⁹ is G.

Aspect 201. The IL-2Rα ligand of any one of aspects 176 to 200, whereinX¹⁰ is C.

Aspect 202. The IL-2Rα ligand of any one of aspects 176 to 201, whereinX¹¹ is selected from G, S, R, T, and Y.

Aspect 203. The IL-2Rα ligand of any one of aspects 176 to 202, whereinX¹² is selected from S, G, A, I, G, P, R, and S.

Aspect 204. The IL-2Rα ligand of any one of aspects 176 to 203, whereinX¹ is selected from F, W, and Y.

Aspect 205. The IL-2Rα ligand of any one of aspects 176 to 204, whereinX² is V.

Aspect 206. The IL-2Rα ligand of any one of aspects 176 to 205, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 207. The IL-2Rα ligand of any one of aspects 176 to 206, whereinX⁴ is C.

Aspect 208. The IL-2Rα ligand of any one of aspects 176 to 207, whereinX⁵ is selected from A, G, P, S, and T.

Aspect 209. The IL-2Rα ligand of any one of aspects 176 to 208, whereinX⁵ is selected from H, K, and R.

Aspect 210. The IL-2Rα ligand of any one of aspects 176 to 209, whereinX⁵ is S.

Aspect 211. The IL-2Rα ligand of any one of aspects 176 to 210, whereinX⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 212. The IL-2Rα ligand of any one of aspects 176 to 211, whereinX⁶ is W.

Aspect 213. The IL-2Rα ligand of any one of aspects 176 to 212, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 214. The IL-2Rα ligand of any one of aspects 176 to 213, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 215. The IL-2Rα ligand of any one of aspects 176 to 214, whereinX⁹ is G.

Aspect 216. The IL-2Rα ligand of any one of aspects 176 to 215, whereinX¹⁰ is C.

Aspect 217. The IL-2Rα ligand of any one of aspects 176 to 216, whereinX¹¹ is R.

Aspect 218. The IL-2Rα ligand of any one of aspects 176 to 217, whereinX¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 219. The IL-2Rα ligand of aspect 176, wherein X² is V, X⁴ is C,X⁵ is S, X⁹ is G,

X¹⁰ is C, and X¹¹ is R.

Aspect 220. The IL-2Rα ligand of aspect 176, wherein,

X¹ is selected from F, H, I, L, M, V, W, and Y;

X² is V;

X³ is selected from F, I, L, M, V, W, and Y;

X⁴ is C;

X⁵ is S;

X⁶ is selected from F, I, L, M, V, W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is G;

X¹⁰ is C;

X¹¹ is R; and

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 221. The IL-2Rα ligand of aspect 176, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 41to SEQ ID NO: 45:

SEQ ID NO: 41 Y V L C S N R N G C R P SEQ ID NO: 42 Y V T C R W G Y G CT R SEQ ID NO: 43 W V A C S W D H G C R S SEQ ID NO: 44 H V I C S V N GG C R G SEQ ID NO: 45 W V X C K P L H G C Y G

Aspect 222. The IL-2Rα ligand of any one of aspects 176 to 221, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 223. The IL-2Rα ligand of any one of aspects 221 to 222, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 224. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (6a) (SEQ IDNO: 46), the amino acid sequence of Formula (6b) (SEQ ID NO: 47), theamino acid sequence of Formula (6c) (SEQ ID NO: 48), or the amino acidsequence of Formula (6d) (SEQ ID NO: 49):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (6a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—  (6b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—X¹⁴—  (6c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (6d)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid;    -   X³ is selected from an amino acid comprising a large hydrophobic        side chain or an aromatic side chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a basic side chain;    -   X⁷ is selected from an amino acid comprising a small hydrophobic        side chain or a polar neutral side chain;    -   X⁸ is selected from an amino acid comprising an acidic side        chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹² is C;    -   X¹³ is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X¹⁴ is selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain; and    -   X¹⁵ is selected from an amino acid.

Aspect 225. The IL-2Rα ligand of aspect 224, wherein,

-   -   X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S,        T, V, W, and Y;    -   X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S,        T, V, W, and Y;    -   X³ is selected from F, H, I, L, M, V, W, and Y;    -   X⁴ is C;    -   X⁵ is selected from F, I, L, M, V, W, and Y;    -   X⁶ is selected from H, K, and R;    -   X⁷ is selected from A, G, H, N, P, Q, S, T, and Y;    -   X⁸ is selected from D and E;    -   X⁹ is selected from A, G, P, S, and T;    -   X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,        S, T, V, W, and Y;    -   X¹¹ is selected from A, G, P, S, and T;    -   X¹² is C;    -   X¹³ is selected from F, H, I, L, M, V, W, and Y;    -   X¹⁴ is selected from A, G, H, N, P, Q, S, T, and Y; and    -   X¹⁵ is selected from any A, D, E, F, G, H, I, K, L, M, N, P, Q,        R, S, T, V, W, and Y.

Aspect 226. The IL-2Rα ligand f any one of aspects 224 to 225, whereinX¹ is selected from E, K, R, T, and L.

Aspect 227. The IL-2Rα ligand of any one of aspects 224 to 226, whereinX² is selected from Q, Y, V, K, and R.

Aspect 228. The IL-2Rα ligand of any one of aspects 224 to 227, whereinX³ is selected from F, W, V, and L.

Aspect 229. The IL-2Rα ligand of any one of aspects 224 to 228, whereinX⁴ is C.

Aspect 230. The IL-2Rα ligand of any one of aspects 224 to 229, whereinX⁵ is L.

Aspect 231. The IL-2Rα ligand of any one of aspects 224 to 230, whereinX⁶ is selected from V, R, A, and K.

Aspect 232. The IL-2Rα ligand of any one of aspects 224 to 231, whereinX⁷ is S.

Aspect 233. The IL-2Rα ligand of any one of aspects 224 to 232, whereinX⁸ is selected from D and E.

Aspect 234. The IL-2Rα ligand of any one of aspects 224 to 233, whereinX⁹ is P.

Aspect 235. The IL-2Rα ligand of any one of aspects 224 to 234, whereinX¹⁰ is selected from M, D, N, M Q, and T.

Aspect 236. The IL-2Rα ligand of any one of aspects 224 to 235, whereinX¹¹ is selected from A and S.

Aspect 237. The IL-2Rα ligand of any one of aspects 224 to 236, whereinX¹² is C.

Aspect 238. The IL-2Rα ligand of any one of aspects 224 to 237, whereinX¹³ is selected from F and W.

Aspect 239. The IL-2Rα ligand of any one of aspects 224 to 238, whereinX¹⁴ is selected from S, A, and I.

Aspect 240. The IL-2Rα ligand of any one of aspects 224 to 239, whereinX¹⁵ is selected from L, T, M, and V.

Aspect 241. The IL-2Rα ligand of any one of aspects 224 to 240, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 242. The IL-2Rα ligand of any one of aspects 224 to 241, whereinX² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 243. The IL-2Rα ligand of any one of aspects 224 to 242, whereinX³ is selected from F, W, and Y.

Aspect 244. The IL-2Rα ligand of any one of aspects 224 to 243, whereinX⁴ is C.

Aspect 245. The IL-2Rα ligand of any one of aspects 224 to 244, whereinX⁵ is L.

Aspect 246. The IL-2Rα ligand of any one of aspects 224 to 245, whereinX⁶ is selected from H, K, and R.

Aspect 247. The IL-2Rα ligand of any one of aspects 224 to 246, whereinX⁷ is S.

Aspect 248. The IL-2Rα ligand of any one of aspects 224 to 247, whereinX⁸ is selected from D and E.

Aspect 249. The IL-2Rα ligand of any one of aspects 224 to 248, whereinX⁹ is P.

Aspect 250. The IL-2Rα ligand of any one of aspects 224 to 249, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 251. The IL-2Rα ligand of any one of aspects 224 to 250, whereinX¹¹ is A.

Aspect 252. The IL-2Rα ligand of any one of aspects 224 to 251, whereinX¹² is C.

Aspect 253. The IL-2Rα ligand of any one of aspects 224 to 252, whereinX¹³ is selected from F, W, and Y.

Aspect 254. The IL-2Rα ligand of any one of aspects 224 to 252, whereinX¹³ is W.

Aspect 255. The IL-2Rα ligand of any one of aspects 224 to 254, whereinX¹⁴ is S.

Aspect 256. The IL-2Rα ligand of any one of aspects 224 to 255, whereinX¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 257. The IL-2Rα ligand of aspect 224, wherein X⁴ is C, X⁵ is L,X⁷ is S, X⁸ is E,

X⁹ is P, X¹¹ is A, X¹² is C, X¹² is W, and X¹⁴ is S.

Aspect 258. The IL-2Rα ligand of aspect 224, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is selected from F, H, I, L, M, V, W, and Y;

X⁴ is C;

X⁵ is L;

X⁶ is selected from H, K, and R;

X⁷ is S;

X⁸ is E;

X⁹ is P;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is A;

X¹² is C;

X¹¹ is W;

X¹⁴ is S; and

X¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 259. The IL-2Rα ligand of aspect 224, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 50to SEQ ID NO: 54:

SEQ ID NO: 50 E Q F C L V S D P M A C W S L SEQ ID NO: 51K Y W C L R S E P D A C F A T SEQ ID NO: 52R V Y C L A S E P N S C W S T SEQ ID NO: 53T K L C L K S E P Q A C W S M SEQ ID NO: 54I R F C L R S E P T A C W I V

Aspect 260. The IL-2Rα ligand of any one of aspects 224 to 259, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 261. The IL-2Rα ligand of any one of aspects 259 to 260, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 262. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (7a) (SEQ IDNO: 55), the amino acid sequence of Formula (7b) (SEQ ID NO: 56), theamino acid sequence of Formula (7c) (SEQ ID NO: 57), or the amino acidsequence of Formula (7d) (SEQ ID NO: 58):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (7a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—  (7b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—X¹⁴—  (7c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (7d)

wherein,

-   -   X¹ is selected from a basic amino acid;    -   X² is selected from a basic amino acid;    -   X³ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a basic side chain;    -   X⁷ is selected from an amino acid comprising a small hydrophobic        side chain or a polar neutral side chain;    -   X⁸ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹¹ is selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹² is C;    -   X¹³ is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X¹⁴ is selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain; and    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 263. The IL-2Rα ligand of aspect 262, wherein,

X¹ is selected from K, and R;

X² is selected from H, K, and R;

X³ is selected from F, I, L, M, V, W, and Y;

X⁴ is C;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from H, K, and R;

X⁷ is selected from A, G, H, N, P, Q, S, T, and Y;

X⁸ is selected from F, I, L, M, V, W, and Y;

X⁹ is selected from A, G, P, S, and T;

X¹⁰ is selected from A, G, H, N, P, Q, S, T, and Y;

X¹¹ is selected from A, G, P, S, and T;

X¹² is C;

X¹³ is selected from F, H, I, L, M, V, W, and Y;

X¹⁴ is selected from A, G, H, N, P, Q, S, T, and Y; and

X¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 264. The IL-2Rα ligand of any one of aspects 262 to 263, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 265. The IL-2Rα ligand of any one of aspects 262 to 264, whereinX² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 266. The IL-2Rα ligand of any one of aspects 262 to 265, whereinX³ is selected from F, I, L, M, V, W, and Y.

Aspect 267. The IL-2Rα ligand of any one of aspects 262 to 266, whereinX⁴ is C.

Aspect 268. The IL-2Rα ligand of any one of aspects 262 to 267, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 269. The IL-2Rα ligand of any one of aspects 262 to 268, whereinX⁵ is L.

Aspect 270. The IL-2Rα ligand of any one of aspects 262 to 269, whereinX⁶ is selected from H, K, and R.

Aspect 271. The IL-2Rα ligand of any one of aspects 262 to 270, whereinX⁷ is selected from A, G, P, S, and T.

Aspect 272. The IL-2Rα ligand of any one of aspects 262 to 271, whereinX⁷ is selected from H, N, Q, S, T, and Y.

Aspect 273. The IL-2Rα ligand of any one of aspects 262 to 272, whereinX⁷ is S.

Aspect 274. The IL-2Rα ligand of any one of aspects 262 to 273, whereinX⁸ is selected from D and E.

Aspect 275. The IL-2Rα ligand of any one of aspects 262 to 274, whereinX⁹ is P.

Aspect 276. The IL-2Rα ligand of any one of aspects 262 to 275, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 277. The IL-2Rα ligand of any one of aspects 262 to 276, whereinX¹¹ is A.

Aspect 278. The IL-2Rα ligand of any one of aspects 262 to 277, whereinX¹² is C.

Aspect 279. The IL-2Rα ligand of any one of aspects 262 to 278, whereinX¹³ is W.

Aspect 280. The IL-2Rα ligand of any one of aspects 262 to 279, whereinX¹⁴ is S.

Aspect 281. The IL-2Rα ligand of any one of aspects 262 to 280, whereinX¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 282. The IL-2Rα ligand of any one of aspects 262 to 281, whereinX¹ is R.

Aspect 283. The IL-2Rα ligand of any one of aspects 262 to 282, whereinX² is R.

Aspect 284. The IL-2Rα ligand of any one of aspects 262 to 283, whereinX³ is F.

Aspect 285. The IL-2Rα ligand of any one of aspects 262 to 284, whereinX⁴ is C.

Aspect 286. The IL-2Rα ligand of any one of aspects 262 to 285, whereinX⁵ is L.

Aspect 287. The IL-2Rα ligand of any one of aspects 262 to 286, whereinX⁶ is R.

Aspect 288. The IL-2Rα ligand of any one of aspects 262 to 287, whereinX⁷ is S.

Aspect 289. The IL-2Rα ligand of any one of aspects 262 to 288, whereinX⁸ is E.

Aspect 290. The IL-2Rα ligand of any one of aspects 262 to 289, whereinX⁹ is P.

Aspect 291. The IL-2Rα ligand of any one of aspects 262 to 290, whereinX¹⁰ is T.

Aspect 292. The IL-2Rα ligand of any one of aspects 262 to 291, whereinX¹¹ is A.

Aspect 293. The IL-2Rα ligand of any one of aspects 262 to 292, whereinX¹² is C.

Aspect 294. The IL-2Rα ligand of any one of aspects 262 to 293, whereinX¹³ is W.

Aspect 295. The IL-2Rα ligand of any one of aspects 262 to 294, whereinX¹⁴ is T.

Aspect 296. The IL-2Rα ligand of any one of aspects 262 to 295, whereinX¹⁵ is V.

Aspect 297. The IL-2Rα ligand of aspect 262, wherein X¹ is R, X² is R,X³ is F, X⁴ is C,

X⁵ is L, X⁶, is R, X⁷ is S, X is E, X⁹ is P, X¹⁰ is T, X¹¹ is A, X¹² isC, X¹¹ is W, and X¹⁵ is V.

Aspect 298. The IL-2Rα ligand of aspect 262, wherein,

X¹ is selected from K and R;

X² is R;

X³ is F;

X⁴ is C;

X⁵ is L;

X⁶ is R;

X⁷ is S;

X⁸ is E;

X⁹ is P;

X¹⁰ is T;

X¹¹ is A;

X¹² is C;

X¹³ is W;

X¹⁴ is T; and

X¹⁵ is V.

Aspect 299. The IL-2Rα ligand of aspect 262, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 59to SEQ ID NO: 68:

SEQ ID NO: 59 R R F C L R S E P T A C W I V SEQ ID NO: 60K L F C L R S G D R A C W V V SEQ ID NO: 61M R F C L R S E P T A C W T V SEQ ID NO: 62R R F C L R S E P T A C W D V SEQ ID NO: 63R R F C L R S D P T A C W I V SEQ ID NO: 64K R F C L R S E P T A C W T V SEQ ID NO: 65R R F C L R S E P M A C W T V SEQ ID NO: 66R R F C L R S E P T A C W T V SEQ ID NO: 67R R F C L R S E P A A C W F V SEQ ID NO: 68R R F C L R S E P T A C W Y V

Aspect 300. The IL-2Rα ligand of any one of aspects 262 to 299, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 301. The IL-2Rα ligand of any one of aspects 299 to 300, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 302. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (8a) (SEQ IDNO: 69), the amino acid sequence of Formula (8b) (SEQ ID NO: 70), or theamino acid sequence of Formula (8c) (SEQ ID NO: 71):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—  (8a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—C—X¹³—  (8b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—  (8c)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid comprising a basic side chain;    -   X³ is C;    -   X⁴ is selected from an amino acid comprising a large hydrophobic        side chain or a basic side chain;    -   X⁵ is selected from an amino acid;    -   X⁶ is selected from an amino acid comprising an acidic side        chain;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid;    -   X¹⁰ is selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹¹ is selected from an amino acid;    -   X¹² is C;    -   X¹³ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁴ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 303. The IL-2Rα ligand of aspect 302, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from H, K, and R;

X³ is C;

X⁴ is selected from F, H, I, K, L, M, R, V, W, and Y;

X⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁶ is selected from D and E;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is selected from A, G, P, S, and T;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is C;

X¹³ is selected from F, I, L, M, V, W, and Y; and

X¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 304. The IL-2Rα ligand of any one of aspects 302 to 303, whereinX¹ is selected from R, I, L, M, N, S, T, V, and D.

Aspect 305. The IL-2Rα ligand of any one of aspects 302 to 304, whereinX² is selected from S, K, R, H, G, and F.

Aspect 306. The IL-2Rα ligand of any one of aspects 302 to 305, whereinX³ is C.

Aspect 307. The IL-2Rα ligand of any one of aspects 302 to 306, whereinX⁴ is selected from N, R, I, T, V, L, and D.

Aspect 308. The IL-2Rα ligand of any one of aspects 302 to 307, whereinX⁵ is selected from R, V, L, M, V, G, Y, I, F, and T.

Aspect 309. The IL-2Rα ligand of any one of aspects 302 to 308, whereinX⁵ is selected from Y, L, E, D, S, I, Y, D, and R.

Aspect 310. The IL-2Rα ligand of any one of aspects 302 to 308, whereinX⁶ is selected from Y, L, E, D, S, and R.

Aspect 311. The IL-2Rα ligand of any one of aspects 302 to 310, whereinX⁷ is selected from G, E, K, T, P, W, L, Y, G, S, and R.

Aspect 312. The IL-2Rα ligand of any one of aspects 302 to 311, whereinX⁸ is selected from I, A, Q, R, S R, L, N, P, A, I, R, D, and W.

Aspect 313. The IL-2Rα ligand of any one of aspects 302 to 312, whereinX⁹ is selected from W, G, S, D, R, L, F, P, A, and T.

Aspect 314. The IL-2Rα ligand of any one of aspects 302 to 313, whereinX¹⁰ is selected from G, T, E, W, Q, R, and Y.

Aspect 315. The IL-2Rα ligand of any one of aspects 302 to 314, whereinX¹¹ is selected from H, P, I, T, H, A, S, F, and Y.

Aspect 316. The IL-2Rα ligand of any one of aspects 302 to 315, whereinX¹² is C.

Aspect 317. The IL-2Rα ligand of any one of aspects 302 to 316, whereinX¹³ is selected from D, V, L, I, Y, I, R, H, T, I, and W.

Aspect 318. The IL-2Rα ligand of any one of aspects 302 to 317, whereinX¹⁴ is selected from T, S, F, and I.

Aspect 319. The IL-2Rα ligand of any one of aspects 302 to 318, whereinX¹ is selected from R, I, L, M, N, S, T, V, and D.

Aspect 320. The IL-2Rα ligand of any one of aspects 302 to 319, whereinX² is selected from S, K, R, H, G, and F.

Aspect 321. The IL-2Rα ligand of any one of aspects 302 to 320, whereinX³ is C.

Aspect 322. The IL-2Rα ligand of any one of aspects 302 to 321, whereinX⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 323. The IL-2Rα ligand of any one of aspects 302 to 321, whereinX⁴ is selected from H, K, and R.

Aspect 324. The IL-2Rα ligand of any one of aspects 302 to 323, whereinX⁵ is selected from Y, L, E, D, S, I, Y, D, and R.

Aspect 325. The IL-2Rα ligand of any one of aspects 302 to 324, whereinX⁶ is selected from Y, L, E, D, S, and R.

Aspect 326. The IL-2Rα ligand of any one of aspects 302 to 324, whereinX⁶ is selected from D and E.

Aspect 327. The IL-2Rα ligand of any one of aspects 302 to 326, whereinX⁷ is selected from G, E, K, T, P, W, L, Y, G, S, and R.

Aspect 328. The IL-2Rα ligand of any one of aspects 302 to 327, whereinX⁸ is selected from I, A, Q, R, S R, L, N, P, A, I, R, D, and W.

Aspect 329. The IL-2Rα ligand of any one of aspects 302 to 328, whereinX⁹ is selected from W, G, S, D, R, L, F, P, A, and T.

Aspect 330. The IL-2Rα ligand of any one of aspects 302 to 329, whereinX¹⁰ is selected from G, T, E, W, Q, R, and Y.

Aspect 331. The IL-2Rα ligand of any one of aspects 302 to 329, whereinX¹⁰ is G.

Aspect 332. The IL-2Rα ligand of any one of aspects 302 to 331, whereinX¹¹ is selected from H, P, I, T, H, A, S, F, and Y.

Aspect 333. The IL-2Rα ligand of any one of aspects 302 to 332, whereinX¹² is C.

Aspect 334. The IL-2Rα ligand of any one of aspects 302 to 333, whereinX¹³ is selected from F, I, L, M, V, W, and Y.

Aspect 335. The IL-2Rα ligand of any one of aspects 302 to 334, whereinX¹⁴ is F.

Aspect 336. The IL-2Rα ligand of aspect 302, wherein X² is R, X³ is C,X⁶, is D, X¹⁰ is G,

X¹² is C, and X¹⁴ is F.

Aspect 337. The IL-2Rα ligand of aspect 302, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is R;

X³ is C;

X⁴ is selected from F, H, I, K, L, M, R, V, W, and Y;

X⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁶ is D;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is G;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is C;

X¹³ is selected from F, I, L, M, V, W, and Y; and

X¹⁴ is F.

Aspect 338. The IL-2Rα ligand of aspect 302, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 72to SEQ ID NO: 86:

SEQ ID NO: 72 R S C N R Y G I W G H C D T SEQ ID NO: 73I K C R V L E A G T P C V F SEQ ID NO: 74 I R C R Y E K Q S G I C L FSEQ ID NO: 75 L R C R L D T R D G T C R F SEQ ID NO: 76M R C I L S P S R E H C L F SEQ ID NO: 77 N H C T M D W R L G A C I FSEQ ID NO: 78 S G C R L S L L D G H C Y F SEQ ID NO: 79S K C V Y D Y N F G T C I F SEQ ID NO: 80 S R C V M S L Q L G A C I FSEQ ID NO: 81 T R C T V I G P P W S C R F SEQ ID NO: 82V F C I G Y G A A Q S C H S SEQ ID NO: 83 V R C L Y D S I T R T C T FSEQ ID NO: 84 V S C K I D R R S G S C L F SEQ ID NO: 85V S C R F R P D L G F C I F SEQ ID NO: 86 D R C D T R T W G Y Y C W I

Aspect 339. The IL-2Rα ligand of any one of aspects 302 to 338, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 340. The IL-2Rα ligand of any one of aspects 338 to 339, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 341. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (9a) (SEQ IDNO: 87), the amino acid sequence of Formula (9b) (SEQ ID NO: 88), theamino acid sequence of Formula (9c) (SEQ ID NO: 89), or the amino acidsequence of Formula (9d) (SEQ ID NO: 90):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (9a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (9b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (9c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (9d)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid comprising a large hydrophobic        side chain or an acidic side chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain or a basic side chain;    -   X⁶ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain;    -   X¹¹ is selected from an amino acid comprising a basic side chain        or an acidic side chain;    -   X¹² is selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹³ is C;    -   X¹⁴ is selected from an amino acid;    -   X¹⁵ is selected from an amino acid; and    -   X¹⁶ is selected from an amino acid.

Aspect 342. The IL-2Rα ligand of aspect 341, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from F, I, L, M, V, W, and Y;

X³ is selected from D, E, F, I, L, M, V, W, and Y;

X⁴ is C;

X⁵ is selected from F, H, I, K, L, M, R, V, W, and Y;

X⁶ is selected from F, I, L, M, V, W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, G, P, S, and T;

X⁹ is selected from A, G, P, S, and T;

X¹⁰ is selected from F, H, I, K, L, M, R, V, W, and Y;

X¹¹ is selected from D, E, H, K, and R;

X¹² is selected from A, G, H, N, P, Q, S, T, and Y;

X¹³ is C;

X¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; and

X¹⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 343. The IL-2Rα ligand of any one of aspects 341 to 342, whereinX¹ is selected from G, E, F, K, P, Q, R, S, and V.

Aspect 344. The IL-2Rα ligand of any one of aspects 341 to 343, whereinX² is selected from S, W, I, F, L, and R.

Aspect 345. The IL-2Rα ligand of any one of aspects 341 to 344, whereinX³ is selected from R, E, I, V, S, N, F, L, and M.

Aspect 346. The IL-2Rα ligand of any one of aspects 341 to 345, whereinX⁴ is C.

Aspect 347. The IL-2Rα ligand of any one of aspects 341 to 346, whereinX⁵ is selected from Y, R, V, T, E, I, and K.

Aspect 348. The IL-2Rα ligand of any one of aspects 341 to 347, whereinX⁶ is selected from W, F, Y, L, H, I, T, S, and V.

Aspect 349. The IL-2Rα ligand of any one of aspects 341 to 348, whereinX⁷ is selected from D, L, S, D, V, Y, S, Q, I, R, M, G, and A.

Aspect 350. The IL-2Rα ligand of any one of aspects 341 to 349, whereinX⁸ is P.

Aspect 351. The IL-2Rα ligand of any one of aspects 341 to 350, whereinX⁹ is G.

Aspect 352. The IL-2Rα ligand of any one of aspects 341 to 351, whereinX¹⁰ is selected from R, S, T, N, R, V, L, H, W, and Y.

Aspect 353. The IL-2Rα ligand of any one of aspects 341 to 352, whereinX¹¹ is selected from E, R, H, G, E, K, Q, and V.

Aspect 354. The IL-2Rα ligand of any one of aspects 341 to 353, whereinX¹² is selected from V, G, S, A, and W.

Aspect 355. The IL-2Rα ligand of any one of aspects 341 to 354, whereinX¹³ is C.

Aspect 356. The IL-2Rα ligand of any one of aspects 341 to 355, whereinX¹⁴ is selected from I, S, R, W, H, V, K, T, R, G, and P.

Aspect 357. The IL-2Rα ligand of any one of aspects 341 to 356, whereinX¹⁵ is selected from F, L, M, S, W, T, A, and R.

Aspect 358. The IL-2Rα ligand of any one of aspects 341 to 357, whereinX¹⁶ is selected from K, F, V, I, F, M, L, Q, T, and N.

Aspect 359. The IL-2Rα ligand of any one of aspects 341 to 358, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 360. The IL-2Rα ligand of any one of aspects 341 to 359, whereinX² is selected from F, W, and Y.

Aspect 361. The IL-2Rα ligand of any one of aspects 341 to 360, whereinX³ is W.

Aspect 362. The IL-2Rα ligand of any one of aspects 341 to 361, whereinX⁴ is C.

Aspect 363. The IL-2Rα ligand of any one of aspects 341 to 362, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 364. The IL-2Rα ligand of any one of aspects 341 to 362, whereinX⁵ is selected from D and E.

Aspect 365. The IL-2Rα ligand of any one of aspects 341 to 364, whereinX⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 366. The IL-2Rα ligand of any one of aspects 341 to 364, whereinX⁶ is selected from F, W, and Y.

Aspect 367. The IL-2Rα ligand of any one of aspects 341 to 366, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 368. The IL-2Rα ligand of any one of aspects 341 to 367, whereinX⁸ is P.

Aspect 369. The IL-2Rα ligand of any one of aspects 341 to 368, whereinX⁹ is G.

Aspect 370. The IL-2Rα ligand of any one of aspects 341 to 369, whereinX¹⁰ is selected from F, I, L, M, V, W, and Y.

Aspect 371. The IL-2Rα ligand of any one of aspects 341 to 369, whereinX¹⁰ is selected from F, W, and Y.

Aspect 372. The IL-2Rα ligand of any one of aspects 341 to 371, whereinX¹⁰ is selected from H, K, and R.

Aspect 373. The IL-2Rα ligand of any one of aspects 341 to 372, whereinX¹¹ is selected from H, K, and R.

Aspect 374. The IL-2Rα ligand of any one of aspects 341 to 372, whereinX¹¹ is selected from D and E.

Aspect 375. The IL-2Rα ligand of any one of aspects 341 to 374, whereinX¹² is selected from A, G, P, S, and T.

Aspect 376. The IL-2Rα ligand of any one of aspects 341 to 374, whereinX¹² is selected from N, Q, S, T, and Y.

Aspect 377. The IL-2Rα ligand of any one of aspects 341 to 376, whereinX¹³ is C.

Aspect 378. The IL-2Rα ligand of any one of aspects 341 to 377, whereinX¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 379. The IL-2Rα ligand of any one of aspects 341 to 378, whereinX¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 380. The IL-2Rα ligand of any one of aspects 341 to 379, whereinX¹⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 381. The IL-2Rα ligand of any one of aspects 341 to 379, whereinX¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 382. The IL-2Rα ligand of any one of aspects 341 to 379, whereinX¹⁶ is selected from F, W, and Y.

Aspect 383. The IL-2Rα ligand of aspect 341, wherein X² is W, X³ is E,X⁴ is C, X⁵, is R,

X⁸ is P, X⁹ is G, X¹⁰ is R, X¹ is R, X¹² is G, and X¹¹ is C.

Aspect 384. The IL-2Rα ligand of aspect 341, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is W;

X³ is E;

X⁴ is C;

X⁵ is R;

X⁶ is selected from F, H, I, L, M, V, W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is P;

X⁹ is G

X¹⁰ is R;

X¹¹ is R;

X¹² is G;

X¹³ is C;

X¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; and

X¹⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 385. The IL-2Rα ligand of aspect 341, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 91to SEQ ID NO: 104:

SEQ ID NO: 91 G S R C Y W D P G R E V C I F K SEQ ID NO: 92E W E C R F L P G R R G C S L F SEQ ID NO: 93F W E C V Y S P G S R G C R M V SEQ ID NO: 94G F R C T Y D P G T H S C W S I SEQ ID NO: 95K W I C R L V P G N G A C H S F SEQ ID NO: 96P W V C E H Y P G R R G C V L M SEQ ID NO: 97Q W S C V F S P G V R G C K L V SEQ ID NO: 98R F I C R I Q P G R E G C W S L SEQ ID NO: 99R W E C I Y I P G R K G C T L Q SEQ ID NO: 100S L N C K T R P G L R W C T W T SEQ ID NO: 101S W E C V Y M P G H Q G C R L F SEQ ID NO: 102V R F C R S G P G W V S C G T Q SEQ ID NO: 103V R L C R V G P G Y E S C P A N SEQ ID NO: 104V R M C Y V A P G Y V S C P R M

Aspect 386. The IL-2Rα ligand of any one of aspects 341 to 385, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 387. The IL-2Rα ligand of any one of aspects 385 to 386, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 388. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (10a) (SEQ IDNO: 105), the amino acid sequence of Formula (10b) (SEQ ID NO: 106), theamino acid sequence of Formula (10c) (SEQ ID NO: 107), or the amino acidsequence of Formula (10d) (SEQ ID NO: 108):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (10a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (10b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (10c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (10d)

wherein,

-   -   X¹ is selected from an amino acid comprising an acidic side        chain;    -   X² is selected from an amino acid comprising a large hydrophobic        side chain;    -   X³ is selected from an amino acid comprising an acidic side        chain;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁷ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁸ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid comprising a basic side        chain;    -   X¹¹ is selected from an amino acid comprising a basic side        chain;    -   X¹² is selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹³ is C;    -   X¹⁴ is selected from an amino acid comprising a small        hydrophobic side chain or a polar neutral side chain;    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 389. The IL-2Rα ligand of aspect 388, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from F, I, L, M, V, W, and Y;

X³ is selected from D and E;

X⁴ is C;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from F, I, L, M, V, W, and Y;

X⁷ is selected from F, I, L, M, V, W, and Y;

X⁸ is selected from A, G, P, S, and T;

X⁹ is selected from A, G, P, S, and T;

X¹⁰ is selected from H, K, and R;

X¹¹ is selected from H, K, and R;

X¹² is selected from A, G, P, S, and T;

X¹³ is C;

X¹⁴ is selected from A, G, H, N, P, Q, S, T, and Y;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 390. The IL-2Rα ligand of any one of aspects 388 to 389, whereinX¹ is selected from N, D, E, A, V, and T.

Aspect 391. The IL-2Rα ligand of any one of aspects 388 to 390, whereinX² is selected from W and Y.

Aspect 392. The IL-2Rα ligand of any one of aspects 388 to 391, whereinX³ is selected from E, H, and D.

Aspect 393. The IL-2Rα ligand of any one of aspects 388 to 392, whereinX⁴ is C.

Aspect 394. The IL-2Rα ligand of any one of aspects 388 to 393, whereinX⁵ is selected from I, 1, W, and V.

Aspect 395. The IL-2Rα ligand of any one of aspects 388 to 394, whereinX⁶ is selected from F and I.

Aspect 396. The IL-2Rα ligand of any one of aspects 388 to 395, whereinX⁷ is selected from S, L, and M.

Aspect 397. The IL-2Rα ligand of any one of aspects 388 to 396, whereinX⁸ is P.

Aspect 398. The IL-2Rα ligand of any one of aspects 388 to 397, whereinX⁹ is G.

Aspect 399. The IL-2Rα ligand of any one of aspects 388 to 398, whereinX¹⁰ is selected from R and H.

Aspect 400. The IL-2Rα ligand of any one of aspects 388 to 399, whereinX¹¹ is selected from R and K.

Aspect 401. The IL-2Rα ligand of any one of aspects 388 to 400, whereinX¹² is G.

Aspect 402. The IL-2Rα ligand of any one of aspects 388 to 401, whereinX¹³ is C.

Aspect 403. The IL-2Rα ligand of any one of aspects 388 to 402, whereinX¹⁴ is selected from S, L, T, and F.

Aspect 404. The IL-2Rα ligand of any one of aspects 388 to 403, whereinX¹⁵ is selected from L and G.

Aspect 405. The IL-2Rα ligand of any one of aspects 388 to 404, whereinX¹⁶ is selected from F, M, T, and I.

Aspect 406. The IL-2Rα ligand of any one of aspects 388 to 405, whereinX¹ is selected from D and E.

Aspect 407. The IL-2Rα ligand of any one of aspects 388 to 406, whereinX² is W.

Aspect 408. The IL-2Rα ligand of any one of aspects 388 to 407, whereinX³ is selected from D and E.

Aspect 409. The IL-2Rα ligand of any one of aspects 388 to 408, whereinX⁴ is C.

Aspect 410. The IL-2Rα ligand of any one of aspects 388 to 409, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 411. The IL-2Rα ligand of any one of aspects 388 to 409, whereinX⁵ is selected from I and L.

Aspect 412. The IL-2Rα ligand of any one of aspects 388 to 411, whereinX⁶ is F.

Aspect 413. The IL-2Rα ligand of any one of aspects 388 to 412, whereinX⁷ is selected from L and M.

Aspect 414. The IL-2Rα ligand of any one of aspects 388 to 413, whereinX⁸ is P.

Aspect 415. The IL-2Rα ligand of any one of aspects 388 to 414, whereinX⁹ is G.

Aspect 416. The IL-2Rα ligand of any one of aspects 388 to 415, whereinX¹⁰ is selected from H and R.

Aspect 417. The IL-2Rα ligand of any one of aspects 388 to 416, whereinX¹¹ is selected from K and R.

Aspect 418. The IL-2Rα ligand of any one of aspects 388 to 417, whereinX¹² is G.

Aspect 419. The IL-2Rα ligand of any one of aspects 388 to 418, whereinX¹³ is C.

Aspect 420. The IL-2Rα ligand of any one of aspects 388 to 419, whereinX¹⁴ is selected from S and T.

Aspect 421. The IL-2Rα ligand of any one of aspects 388 to 420, whereinX¹⁵ is L.

Aspect 422. The IL-2Rα ligand of any one of aspects 388 to 421, whereinX¹⁶ is selected from F and M.

Aspect 423. The IL-2Rα ligand of aspect 388, wherein,

X¹ is D;

X² is W;

X³ is E;

X⁴ is C;

X⁵ is L;

X⁶ is F;

X⁷ is L;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from H and R;

X¹¹ is selected from K and R;

X¹² is G;

X¹³ is C;

X¹⁴ is T;

X¹⁵ is L; and

X¹⁶ is F.

Aspect 424. The IL-2Rα ligand of aspect 388, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 109to SEQ ID NO: 121:

SEQ ID NO: 109 N W E C I F S P G R R G C S L T SEQ ID NO: 110D W E C L F L P G R R G C L L F SEQ ID NO: 111E W E C L F M P G R R G C L L M SEQ ID NO: 112A W E C L F L P G H R G C S L F SEQ ID NO: 113E W E C L F L P G R K G C T L F SEQ ID NO: 114D W E C I F L P G R R G C T L F SEQ ID NO: 115V Y E C L F M P G R K G C F G M SEQ ID NO: 116E W E C W F L P G R R G C T L I SEQ ID NO: 117D W H C L F L P G H R G C T L F SEQ ID NO: 118D W E C L F L P G R R G C T L F SEQ ID NO: 119Y W E C V F M P G H R G C S L I SEQ ID NO: 120T W D C L F L P G R R G C T L M SEQ ID NO: 121N W E C I F S P G R R G C S L T

Aspect 425. The IL-2Rα ligand of any one of aspects 388 to 424, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 426. The IL-2Rα ligand of any one of aspects 424 to 425, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 427. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (11a) (SEQ IDNO: 122), the amino acid sequence of Formula (11b) (SEQ ID NO: 123), theamino acid sequence of Formula (11c) (SEQ ID NO: 124), or the amino acidsequence of Formula (11d) (SEQ ID NO: 125):

—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (11a)

—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (11b)

—X²—X³—C—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—X¹⁵—  (11c)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (11d)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid;    -   X³ is selected from an amino acid;    -   X⁴ is C;    -   X⁵ is selected from an amino acid comprising an acidic side        chain;    -   X⁶ is selected from an amino acid    -   X⁷ is selected from an amino acid comprising an acidic side        chain or an aromatic side chain;    -   X⁸ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid comprising an aromatic chain;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid;    -   X¹³ is C;    -   X¹⁴ is selected from an amino acid;    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 428. The IL-2Rα ligand of aspect 427, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁴ is C;

X⁵ is selected from D and E;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from D, E, F, H, W, and Y;

X⁸ is selected from A, G, P, S, and T;

X⁹ is selected from A, G, P, S, and T;

X¹⁰ is selected from F, H, W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is C;

X¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 429. The IL-2Rα ligand of any one of aspects 427 to 428, whereinX¹ is selected from A, E, F, G, K, R, T, Y, and W.

Aspect 430. The IL-2Rα ligand of any one of aspects 427 to 429, whereinX² is selected from G, T, K, Q, S, L, Q, R, and A.

Aspect 431. The IL-2Rα ligand of any one of aspects 427 to 430, whereinX³ is selected from F, Y, W, and H.

Aspect 432. The IL-2Rα ligand of any one of aspects 427 to 430, whereinX³ is selected from G, W, P, L, R, F, M, V, S, and P.

Aspect 433. The IL-2Rα ligand of any one of aspects 427 to 432, whereinX⁴ is C.

Aspect 434. The IL-2Rα ligand of any one of aspects 427 to 433, whereinX⁵ is selected from K, D, Y, T, Y, Q, F, L, and S.

Aspect 435. The IL-2Rα ligand of any one of aspects 427 to 434, whereinX⁶ is selected from L, D, F, Y, W, N, D, M, V, D, L, and Y.

Aspect 436. The IL-2Rα ligand of any one of aspects 427 to 435, whereinX⁷ is selected from N, H, F, D, N, S, L, and Y.

Aspect 437. The IL-2Rα ligand of any one of aspects 427 to 436, whereinX⁸ is P.

Aspect 438. The IL-2Rα ligand of any one of aspects 427 to 437, whereinX⁹ is G.

Aspect 439. The IL-2Rα ligand of any one of aspects 427 to 438, whereinX¹⁰ is selected from T, H, L, S, Q, R, N, Y, W, V, S, and H.

Aspect 440. The IL-2Rα ligand of any one of aspects 427 to 439, whereinX¹¹ is selected from Q, W, P, D, E, S, P, E, H, G, R, and G.

Aspect 441. The IL-2Rα ligand of any one of aspects 427 to 440, whereinX¹² is selected from V, S, R, I, A, D, S, E, Y, and G.

Aspect 442. The IL-2Rα ligand of any one of aspects 427 to 441, whereinX¹³ is C.

Aspect 443. The IL-2Rα ligand of any one of aspects 427 to 442, whereinX¹⁴ is selected from S, E, T, V, I, D, Q, W, P, I, and Y.

Aspect 444. The IL-2Rα ligand of any one of aspects 427 to 443, whereinX¹⁵ is selected from F, M, W, I, V, T, N, L, and S.

Aspect 445. The IL-2Rα ligand of any one of aspects 427 to 444, whereinX¹⁶ is selected from Y, V, I, L, S, K, E, and R.

Aspect 446. The IL-2Rα ligand of any one of aspects 427 to 445, whereinX⁴ is C.

Aspect 447. The IL-2Rα ligand of any one of aspects 427 to 446, whereinX⁵ is D.

Aspect 448. The IL-2Rα ligand of any one of aspects 427 to 447, whereinX⁷ is selected from D and H.

Aspect 449. The IL-2Rα ligand of any one of aspects 427 to 448, whereinX⁸ is P.

Aspect 450. The IL-2Rα ligand of any one of aspects 427 to 449, whereinX⁹ is G.

Aspect 451. The IL-2Rα ligand of any one of aspects 427 to 450, whereinX¹⁰ is selected from F, H, W, and Y.

Aspect 452. The IL-2Rα ligand of any one of aspects 427 to 451, whereinX¹³ is C.

Aspect 453. The IL-2Rα ligand of any one of aspects 427 to 452, whereinX¹⁵ is selected from F, M, I, W, V, and L.

Aspect 454. The IL-2Rα ligand of any one of aspects 427 to 453, whereinX¹⁶ is selected from Y, V, I, and L.

Aspect 455. The IL-2Rα ligand of aspect 427, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁴ is C;

X⁵ is selected from D and E;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from D, E, H, F, W, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from H, F, W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is C;

X¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 456. The IL-2Rα ligand of aspect 427, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 126to SEQ ID NO: 140:

SEQ ID NO: 126 A G W C K L N P G T Q V C S F Y SEQ ID NO: 127E T P C D L H P G H W S C S M V SEQ ID NO: 128F F L C D D F P G L P R C E W I SEQ ID NO: 129G L R C Y F D P G S Q I C T F L SEQ ID NO: 130G Q R C T Y D P G Q D A C V F S SEQ ID NO: 131G S R C Y W D P G R E V C I F K SEQ ID NO: 132K L W C Q N N P G N S I C D M Y SEQ ID NO: 133K S W C F D H P G Y P I C Q F Y SEQ ID NO: 134R L F C L M N P G P P D C W I Y SEQ ID NO: 135R Q F C L V S P G Y E D C W F V SEQ ID NO: 136T R M C F D D P G W H S C P V V SEQ ID NO: 137T R W C S L H P G V G E C V T L SEQ ID NO: 138T T V C D Y H P G S R Y C I N E SEQ ID NO: 139Y A S C T Y L P G H R G C T L V SEQ ID NO: 140W L P C D D Y P G H G Y C Y S R

Aspect 457. The IL-2Rα ligand of any one of aspects 427 to 456, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 458. The IL-2Rα ligand of any one of aspects 456 to 457, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 459. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (12a) (SEQ IDNO: 141), the amino acid sequence of Formula (12b) (SEQ ID NO: 142), orthe amino acid sequence of Formula (12c) (SEQ ID NO: 143):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (12a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (12b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—  (12c)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid;    -   X³ is C;    -   X⁴ is selected from an amino acid;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid comprising an acidic side        chain, a small hydrophobic side chain, or a polar neutral side        chain;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹³ is C;    -   X¹⁴ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹⁶ is selected from an amino acid.

Aspect 471. The IL-2Rα ligand of aspect 459, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, G, H, N, P, Q, S, T, and Y;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from F, I, L, M, V, W, and Y;

X¹² is selected from F, I, L, M, V, W, and Y;

X¹³ is C;

X¹⁴ is selected from F, I, L, M, V, W, and Y; and

X¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 461. The IL-2Rα ligand of any one of aspects 459 to 460, whereinX¹ is selected from S, N, Q, R, and G.

Aspect 462. The IL-2Rα ligand of any one of aspects 459 to 461, whereinX² is selected from A, H, R, and G.

Aspect 463. The IL-2Rα ligand of any one of aspects 459 to 462, whereinX³ is C.

Aspect 464. The IL-2Rα ligand of any one of aspects 459 to 463, whereinX⁴ is selected from Q, T, N, M, and S.

Aspect 465. The IL-2Rα ligand of any one of aspects 459 to 464, whereinX⁵ is selected from L and R.

Aspect 466. The IL-2Rα ligand of any one of aspects 459 to 465, whereinX⁶ is selected from K, S, R, and V.

Aspect 467. The IL-2Rα ligand of any one of aspects 459 to 466, whereinX⁷ is selected from W, K, and L.

Aspect 468. The IL-2Rα ligand of any one of aspects 459 to 467, whereinX⁸ is selected from D, T, L, Q, and A.

Aspect 469. The IL-2Rα ligand of any one of aspects 459 to 468, whereinX⁹ is selected from E, Y, D, and P.

Aspect 470. The IL-2Rα ligand of any one of aspects 459 to 469, whereinX¹⁰ is selected from G, P, A, E, and S.

Aspect 471. The IL-2Rα ligand of any one of aspects 459 to 470, whereinX¹¹ is selected from W and L.

Aspect 472. The IL-2Rα ligand of any one of aspects 459 to 471, whereinX¹² is selected from T, V, I, and A.

Aspect 473. The IL-2Rα ligand of any one of aspects 459 to 472, whereinX¹³ is C.

Aspect 474. The IL-2Rα ligand of any one of aspects 459 to 473, whereinX¹⁴ is selected from L, V, Q, and I.

Aspect 475. The IL-2Rα ligand of any one of aspects 459 to 474, whereinX¹⁵ is selected from F and A.

Aspect 476. The IL-2Rα ligand of any one of aspects 459 to 475, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 477. The IL-2Rα ligand of any one of aspects 459 to 476, whereinX² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 478. The IL-2Rα ligand of any one of aspects 459 to 477, whereinX³ is C.

Aspect 479. The IL-2Rα ligand of any one of aspects 459 to 478, whereinX⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 480. The IL-2Rα ligand of any one of aspects 459 to 479, whereinX⁵ is L.

Aspect 481. The IL-2Rα ligand of any one of aspects 459 to 480, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 482. The IL-2Rα ligand of any one of aspects 459 to 481, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 483. The IL-2Rα ligand of any one of aspects 459 to 482, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 484. The IL-2Rα ligand of any one of aspects 459 to 483, whereinX⁹ is selected from D and E.

Aspect 485. The IL-2Rα ligand of any one of aspects 459 to 484, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 486. The IL-2Rα ligand of any one of aspects 459 to 485, whereinX¹¹ is selected from F, I, L, M, V, W, and Y.

Aspect 487. The IL-2Rα ligand of any one of aspects 459 to 485, whereinX¹¹ is W.

Aspect 488. The IL-2Rα ligand of any one of aspects 459 to 487, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 489. The IL-2Rα ligand of any one of aspects 459 to 488, whereinX¹³ is C.

Aspect 490. The IL-2Rα ligand of any one of aspects 459 to 489, whereinX¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 491. The IL-2Rα ligand of any one of aspects 459 to 490, whereinX¹⁵ is F.

Aspect 492. The IL-2Rα ligand of aspect 459, wherein X³ is C, X⁵ is L,X⁹ is D or E, X¹¹ is W, X¹³ is C, and X¹⁵ is F.

Aspect 493. The IL-2Rα ligand of aspect 459, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁵ is L;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from D and E;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y:

X¹¹ is selected from F, I, L, M, V, W, and Y;

X¹² is selected from F, I, L, M, V, W, and Y;

X¹³ is C;

X¹⁴ is selected from F, I, L, M, V, W, and Y; and

X¹⁵ is F.

Aspect 494. The IL-2Rα ligand of aspect 459, wherein X³ is C, X⁵ is L,X¹¹ is W, X¹¹ is C, and X¹ is F.

Aspect 495. The IL-2Rα ligand of aspect 459, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 144to SEQ ID NO: 148:

SEQ ID NO: 144 S A C Q L K W D E G W T C L F SEQ ID NO: 145N H C T L S K T Y P W V C V F SEQ ID NO: 146Q R C N R S L L D A L I C Q A SEQ ID NO: 147R G C M L R L Q P E L A C V F SEQ ID NO: 148G G C S L V W A D S W V C I F

Aspect 496. The IL-2Rα ligand of any one of aspects 459 to 495, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 497. The IL-2Rα ligand of any one of aspects 495 to 496, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 498. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (13a) (SEQ IDNO: 149), the amino acid sequence of Formula (13b) (SEQ ID NO: 150), orthe amino acid sequence of Formula (13c) (SEQ ID NO: 151):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (13a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (13b)

—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—  (13c)

wherein,

-   -   X¹ is selected from an amino acid comprising a small hydrophobic        side chain or a basic side chain;    -   X² is selected from an amino acid comprising a small hydrophobic        side chain or a basic side chain;    -   X³ is C;    -   X⁴ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁷ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid comprising an acidic side        chain;    -   X¹⁰ is selected from an amino acid comprising a small        hydrophobic side chain;    -   X¹¹ is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain or an acidic side chain;    -   X¹³ is C;    -   X¹⁴ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 499. The IL-2Rα ligand of aspect 498, wherein,

X¹ is selected from A, G, H, K, P, R, S, and T;

X² is selected from A, G, H, K, P, R, S, and T;

X³ is C;

X⁴ is selected from A, G, P, S, and T;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from F, I, L, M, V, W, and Y;

X⁷ is selected from F, I, L, M, V, W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from D and E;

X¹⁰ is selected from A, G, P, S, and T;

X¹¹ is selected from F, I, L, M, V, W, and Y;

X¹² is selected from D, E, F, I, L, M, V, W, and Y;

X¹³ is C;

X¹⁴ is selected from F, I, L, M, V, W, and Y; and

X¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 500. The IL-2Rα ligand of any one of aspects 498 to 499, whereinX¹ is selected from S, R, Q, V, A, and G.

Aspect 501. The IL-2Rα ligand of any one of aspects 498 to 500, whereinX² is selected from R, G, A, and S.

Aspect 502. The IL-2Rα ligand of any one of aspects 498 to 501, whereinX³ is C.

Aspect 503. The IL-2Rα ligand of any one of aspects 498 to 502, whereinX⁴ is selected from S, T, Q, and H.

Aspect 504. The IL-2Rα ligand of any one of aspects 498 to 503, whereinX⁵ is L.

Aspect 505. The IL-2Rα ligand of any one of aspects 498 to 504, whereinX⁶ is selected from V, Q, A, and R.

Aspect 506. The IL-2Rα ligand of any one of aspects 498 to 505, whereinX⁷ is selected from W and F.

Aspect 507. The IL-2Rα ligand of any one of aspects 498 to 506, whereinX⁸ is selected from T, D, S, L, A, E, and Q.

Aspect 508. The IL-2Rα ligand of any one of aspects 498 to 507, whereinX⁹ is selected from D, G, and E.

Aspect 509. The IL-2Rα ligand of any one of aspects 498 to 507, whereinX¹⁰ is selected from T, S, R, G, A, S, and N.

Aspect 510. The IL-2Rα ligand of any one of aspects 498 to 508, whereinX¹¹ is W.

Aspect 511. The IL-2Rα ligand of any one of aspects 498 to 510, whereinX¹² is selected from V and E.

Aspect 512. The IL-2Rα ligand of any one of aspects 498 to 511, whereinX¹³ is C.

Aspect 513. The IL-2Rα ligand of any one of aspects 498 to 512, whereinX¹⁴ is selected from V and I.

Aspect 514. The IL-2Rα ligand of any one of aspects 498 to 513, whereinX¹⁵ is F.

Aspect 515. The IL-2Rα ligand of any one of aspects 498 to 514, whereinX¹ is selected from A, G, P, S, and T.

Aspect 516. The IL-2Rα ligand of any one of aspects 498 to 514, whereinX¹ is selected from H, K, and R.

Aspect 517. The IL-2Rα ligand of any one of aspects 498 to 516, whereinX² is selected from A, G, P, S, and T.

Aspect 518. The IL-2Rα ligand of any one of aspects 498 to 516, whereinX² is selected from H, K, and R.

Aspect 519. The IL-2Rα ligand of any one of aspects 498 to 518, whereinX² is selected from R and G.

Aspect 520. The IL-2Rα ligand of any one of aspects 498 to 519, whereinX³ is C.

Aspect 521. The IL-2Rα ligand of any one of aspects 498 to 520, whereinX⁴ is selected from A, G, P, S, and T.

Aspect 522. The IL-2Rα ligand of any one of aspects 498 to 520, whereinX⁴ is selected from S and T.

Aspect 523. The IL-2Rα ligand of any one of aspects 498 to 522, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 524. The IL-2Rα ligand of any one of aspects 498 to 522, whereinX⁵ is L.

Aspect 525. The IL-2Rα ligand of any one of aspects 498 to 524, whereinX⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 526. The IL-2Rα ligand of any one of aspects 498 to 524, whereinX⁶ is V.

Aspect 527. The IL-2Rα ligand of any one of aspects 498 to 526, whereinX⁷ is selected from F, I, L, M, V, W, and Y.

Aspect 528. The IL-2Rα ligand of any one of aspects 498 to 526, whereinX⁷ is selected from F, W, and Y.

Aspect 529. The IL-2Rα ligand of any one of aspects 498 to 526, whereinX⁷ is W.

Aspect 530. The IL-2Rα ligand of any one of aspects 498 to 529, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 531. The IL-2Rα ligand of any one of aspects 498 to 530, whereinX⁸ is selected from A, G, P, S, and T.

Aspect 532. The IL-2Rα ligand of any one of aspects 498 to 530, whereinX⁸ is A.

Aspect 533. The IL-2Rα ligand of any one of aspects 498 to 532, whereinX⁹ is selected from D and E.

Aspect 534. The IL-2Rα ligand of any one of aspects 498 to 532, whereinX⁹ is D.

Aspect 535. The IL-2Rα ligand of any one of aspects 498 to 534, whereinX¹⁰ is selected from A, G, P, S, and T.

Aspect 536. The IL-2Rα ligand of any one of aspects 498 to 534, whereinX¹⁰ is S.

Aspect 537. The IL-2Rα ligand of any one of aspects 498 to 536, whereinX¹¹ is selected from F, I, L, M, V, W, and Y.

Aspect 538. The IL-2Rα ligand of any one of aspects 498 to 536, whereinX¹¹ is selected from F, W, and Y.

Aspect 539. The IL-2Rα ligand of any one of aspects 498 to 536, whereinX¹¹ is W.

Aspect 540. The IL-2Rα ligand of any one of aspects 498 to 539, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 541. The IL-2Rα ligand of any one of aspects 498 to 540, whereinX¹² is selected from D and E.

Aspect 542. The IL-2Rα ligand of any one of aspects 498 to 540, whereinX¹² is selected from V and E.

Aspect 543. The IL-2Rα ligand of any one of aspects 498 to 540, whereinX¹² is V.

Aspect 544. The IL-2Rα ligand of any one of aspects 498 to 543, whereinX¹³ is C.

Aspect 545. The IL-2Rα ligand of any one of aspects 498 to 544, whereinX¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 546. The IL-2Rα ligand of any one of aspects 498 to 544, whereinX¹⁴ is I.

Aspect 547. The IL-2Rα ligand of any one of aspects 498 to 546, whereinX¹⁵ is F.

Aspect 548. The IL-2Rα ligand of aspect 498, wherein X² is R, X³ is C,X⁵ is S, X⁶ is L,

X⁷ is V, X⁸ is W, X¹⁰ is D, X¹¹ is S, X¹² is W, X¹³ is V, X¹⁴ is C, X¹⁵is I, and X¹⁶ is F.

Aspect 549. The IL-2Rα ligand of aspect 498, wherein,

X¹ is selected from A, D, E, G, P, S, and T;

X² is selected from G and R;

X³ is C;

X⁴ is selected from S and T;

X⁵ is L;

X⁶ is V;

X⁷ is selected from F and W;

X⁸ is selected from A, G, P, S, and T;

X⁹ is selected from D and E;

X¹⁰ is S;

X¹¹ is W;

X¹² is V;

X¹³ is C;

X¹⁴ is I; and

X¹⁵ is F.

Aspect 550. The IL-2Rα ligand of aspect 498, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 152to SEQ ID NO: 166:

SEQ ID NO: 152 S R C S L V W T D T W V C V F SEQ ID NO: 153S R C T L V F D D S W V C V F SEQ ID NO: 154R G C S L V W S G S W E C I F SEQ ID NO: 155Q A C Q L V W L D S W V C I F SEQ ID NO: 156V G C S L V W T D R W E C I F SEQ ID NO: 157S G C S L Q W A D G W V C I F SEQ ID NO: 158A R C S L V W D E A W V C I F SEQ ID NO: 159R G C S L V W A G S W E C I F SEQ ID NO: 160S R C S L V W A E N W V C I F SEQ ID NO: 161R R C T L V F L D S W E C I F SEQ ID NO: 162R G C T L A W E D S W V C I F SEQ ID NO: 163R G C S L R F A E A W E C I F SEQ ID NO: 164A S C S L V W Q D S W V C I F SEQ ID NO: 165S R C S L V W A D S W V C I F SEQ ID NO: 166G R C H L V W S D R W E C I F

Aspect 551. The IL-2Rα ligand of any one of aspects 498 to 550, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 552. The IL-2Rα ligand of any one of aspects 550 to 551, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 553. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (14a) (SEQ IDNO: 167), or the amino acid sequence of Formula (14b) (SEQ ID NO: 168):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (14a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (14b)

wherein,

-   -   X¹ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X² is C;    -   X³ is selected from an amino acid comprising a small hydrophobic        side chain;    -   X⁴ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁵ is selected from an amino acid;    -   X⁶ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁷ is selected from an amino acid comprising an acidic side        chain or a polar neutral side chain;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid;    -   X¹⁰ is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹¹ is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain or an acidic side chain;    -   X¹³ is C; and    -   X¹⁴ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 554. The IL-2Rα ligand of aspect 553, wherein,

X¹ is selected from A, G, P, S, and T;

X² is C;

X³ is selected from A, G, P, S, and T;

X⁴ is selected from F, I, L, M, V, W, and Y;

X⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁶ is selected from F, I, L, M, V, W, and Y;

X⁷ is selected from D, E, N, Q, S, T, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is selected from F, I, L, M, V, W, and Y;

X¹¹ is selected from F, I, L, M, V, W, and Y;

X¹¹ is selected from D, E, F, I, L, M, V, W, and Y;

X¹³ is C; and

X¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 555. The IL-2Rα ligand of any one of aspects 553 to 554, whereinX¹ is selected from G and S.

Aspect 556. The IL-2Rα ligand of any one of aspects 553 to 555, whereinX² is C.

Aspect 557. The IL-2Rα ligand of any one of aspects 553 to 556, whereinX³ is selected from T, S, M, and V.

Aspect 558. The IL-2Rα ligand of any one of aspects 553 to 557, whereinX⁴ is selected from L and V.

Aspect 559. The IL-2Rα ligand of any one of aspects 553 to 558, whereinX⁵ is selected from K, R, M, S, T, and Q.

Aspect 560. The IL-2Rα ligand of any one of aspects 553 to 559, whereinX⁶ is selected from W, R, and F.

Aspect 561. The IL-2Rα ligand of any one of aspects 553 to 560, whereinX⁷ is selected from E, D, Q, N, G, and S.

Aspect 562. The IL-2Rα ligand of any one of aspects 553 to 561, whereinX⁸ is selected from S, G, D, Q, K, and G.

Aspect 563. The IL-2Rα ligand of any one of aspects 553 to 562, whereinX⁹ is selected from P, D, G, F, and V.

Aspect 564. The IL-2Rα ligand of any one of aspects 553 to 563, whereinX¹⁰ is selected from N and W.

Aspect 565. The IL-2Rα ligand of any one of aspects 553 to 564, whereinX¹¹ is W.

Aspect 566. The IL-2Rα ligand of any one of aspects 553 to 565, whereinX¹² is selected from T, V, H, and E.

Aspect 567. The IL-2Rα ligand of any one of aspects 553 to 566, whereinX¹³ is C.

Aspect 568. The IL-2Rα ligand of any one of aspects 553 to 567, whereinX¹⁴ is selected from Y, E, I, and V.

Aspect 569. The IL-2Rα ligand of any one of aspects 553 to 568, whereinX¹ is G.

Aspect 570. The IL-2Rα ligand of any one of aspects 553 to 569, whereinX² is C.

Aspect 571. The IL-2Rα ligand of any one of aspects 553 to 570, whereinX³ is selected from S and T.

Aspect 572. The IL-2Rα ligand of any one of aspects 553 to 570, whereinX³ is T.

Aspect 573. The IL-2Rα ligand of any one of aspects 553 to 572, whereinX⁴ is L.

Aspect 574. The IL-2Rα ligand of any one of aspects 553 to 573, whereinX⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 575. The IL-2Rα ligand of any one of aspects 553 to 574, whereinX⁶ is W.

Aspect 576. The IL-2Rα ligand of any one of aspects 553 to 575, whereinX⁷ is selected from D, E, Q, and N.

Aspect 577. The IL-2Rα ligand of any one of aspects 553 to 576, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 578. The IL-2Rα ligand of any one of aspects 553 to 577, whereinX⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 579. The IL-2Rα ligand of any one of aspects 553 to 578, whereinX¹⁰ is W.

Aspect 580. The IL-2Rα ligand of any one of aspects 553 to 579, whereinX¹¹ is W.

Aspect 581. The IL-2Rα ligand of any one of aspects 553 to 580, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 582. The IL-2Rα ligand of any one of aspects 553 to 581, whereinX¹² is selected from D and E.

Aspect 583. The IL-2Rα ligand of any one of aspects 553 to 581, whereinX¹² is selected from E and V.

Aspect 584. The IL-2Rα ligand of any one of aspects 553 to 583, whereinX¹³ is C.

Aspect 585. The IL-2Rα ligand of any one of aspects 553 to 584, whereinX¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 586. The IL-2Rα ligand of any one of aspects 553 to 584, whereinX¹⁴ is selected from I and V.

Aspect 587. The IL-2Rα ligand of aspect 553, wherein X¹ is G, X² is C,X³ is T, X⁴ is L,

X⁶ is W, X¹⁰ is W, X¹¹ is W, and X¹¹ is C.

Aspect 588. The IL-2Rα ligand of aspect 553, wherein,

X¹ is G;

X² is C;

X³ is selected from T and S;

X⁴ is L;

X⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁶ is W;

X⁷ is selected from D, E, N, Q, S, T, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is W;

X¹¹ is W;

X¹² is selected from V and E;

X¹³ is C; and

X¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 589. The IL-2Rα ligand of aspect 553, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 169to SEQ ID NO: 174:

SEQ ID NO: 169 G C T L K W E S P N W T C Y

SEQ ID NO: 170 S C T V R W D G D W W V C E

SEQ ID NO: 171 G C S L M W Q D G W W V C I

SEQ ID NO: 172 G C T L S W N Q G W W H C V

SEQ ID NO: 173 G C M L T R G K F W W E C I

SEQ ID NO: 174 G C V L Q F S G V W W E C V

Aspect 590. The IL-2Rα ligand of any one of aspects 553 to 589, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 591. The IL-2Rα ligand of any one of aspects 589 to 590, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 592. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (15a) (SEQ IDNO: 175), the amino acid sequence of Formula (15b) (SEQ ID NO: 176), orthe amino acid sequence of Formula (15c) (SEQ ID NO: 177):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (15a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (15b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—X¹⁶—  (15c)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid;    -   X³ is C;    -   X⁴ is selected from an amino acid comprising a polar/neutral        side chain or a basic side chain;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid comprising a polar neutral        side chain or a basic side chain;    -   X⁸ is P;    -   X⁹ is G;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid comprising a large        hydrophobic side chain;    -   X¹³ is selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X¹⁴ is C;    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 593. The IL-2Rα ligand of aspect 592, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from H, K, N, Q, R, S, T, and Y;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from H, K, N, Q, R, S, T, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from F, I, L, M, V, W, and Y;

X¹³ is selected from D, E, N, Q, S, T, and Y;

X¹⁴ is C;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 594. The IL-2Rα ligand of any one of aspects 592 to 593, whereinX¹ is selected from Q, A, G, K, L, N, P, Q, S, and T.

Aspect 595. The IL-2Rα ligand of any one of aspects 592 to 594, whereinX² is selected from R, G, K, T, P, A, S, and H.

Aspect 596. The IL-2Rα ligand of any one of aspects 592 to 595, whereinX³ is C.

Aspect 597. The IL-2Rα ligand of any one of aspects 592 to 596, whereinX⁴ is selected from Q, M, S, R, T, I, K, R, H, and L.

Aspect 598. The IL-2Rα ligand of any one of aspects 592 to 597, whereinX⁵ is selected from L, P, M, and V.

Aspect 599. The IL-2Rα ligand of any one of aspects 592 to 598, whereinX⁶ is selected from S, L, R, Q, F, W, N, I, and G.

Aspect 600. The IL-2Rα ligand of any one of aspects 592 to 599, whereinX⁷ is selected from K, H, R, W, L, N, F, and V.

Aspect 601. The IL-2Rα ligand of any one of aspects 592 to 600, whereinX⁸ is selected from S, P, T, and L.

Aspect 602. The IL-2Rα ligand of any one of aspects 592 to 601, whereinX⁹ is G.

Aspect 603. The IL-2Rα ligand of any one of aspects 592 to 602, whereinX¹⁰ is selected from G, L, S, D, T, E, M, N, F, H, R, K, and P.

Aspect 604. The IL-2Rα ligand of any one of aspects 592 to 603, whereinX¹¹ is selected from E, Y, R, G, H, S, I, G, L, W, F, and V.

Aspect 605. The IL-2Rα ligand of any one of aspects 592 to 604, whereinX¹² is selected from L, W, Y, H, and V.

Aspect 606. The IL-2Rα ligand of any one of aspects 592 to 605, whereinX¹³ is selected from G, E, V, T, Q, and A.

Aspect 607. The IL-2Rα ligand of any one of aspects 592 to 606, whereinX¹⁴ is C.

Aspect 608. The IL-2Rα ligand of any one of aspects 592 to 607, whereinX¹⁵ is selected from M, I, V, L, W, R, and F.

Aspect 609. The IL-2Rα ligand of any one of aspects 592 to 609, whereinX¹⁶ is selected from F, S, and G.

Aspect 610. The IL-2Rα ligand of any one of aspects 592 to 609, whereinX¹ is selected from S and T.

Aspect 611. The IL-2Rα ligand of any one of aspects 592 to 610, whereinX² is selected from S, T, R, and K.

Aspect 612. The IL-2Rα ligand of any one of aspects 592 to 611, whereinX³ is C.

Aspect 613. The IL-2Rα ligand of any one of aspects 592 to 612, whereinX⁴ is selected from N, Q, S, T, and Y.

Aspect 614. The IL-2Rα ligand of any one of aspects 592 to 612, whereinX⁴ is T.

Aspect 615. The IL-2Rα ligand of any one of aspects 592 to 614, whereinX⁵ is selected from L, M, and V.

Aspect 616. The IL-2Rα ligand of any one of aspects 592 to 614, whereinX⁵ is L.

Aspect 617. The IL-2Rα ligand of any one of aspects 592 to 616, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 618. The IL-2Rα ligand of any one of aspects 592 to 617, whereinX⁷ is selected from N, K, H, and R.

Aspect 619. The IL-2Rα ligand of any one of aspects 592 to 617, whereinX⁷ is N.

Aspect 620. The IL-2Rα ligand of any one of aspects 592 to 619, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 621. The IL-2Rα ligand of any one of aspects 592 to 620, whereinX⁸ is selected from A, G, P, S, and T.

Aspect 622. The IL-2Rα ligand of any one of aspects 592 to 620, whereinX⁸ is P.

Aspect 623. The IL-2Rα ligand of any one of aspects 592 to 622, whereinX⁹ is G.

Aspect 624. The IL-2Rα ligand of any one of aspects 592 to 623, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 625. The IL-2Rα ligand of any one of aspects 592 to 624, whereinX¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 626. The IL-2Rα ligand of any one of aspects 592 to 625, whereinX¹¹ is selected from A, G, P, S, and T.

Aspect 627. The IL-2Rα ligand of any one of aspects 592 to 625, whereinX¹¹ is G.

Aspect 628. The IL-2Rα ligand of any one of aspects 592 to 627, whereinX¹² is W.

Aspect 629. The IL-2Rα ligand of any one of aspects 592 to 628, whereinX¹³ is selected from N, Q, S, T, and Y.

Aspect 630. The IL-2Rα ligand of any one of aspects 592 to 628, whereinX¹³ is selected from D and E.

Aspect 631. The IL-2Rα ligand of any one of aspects 592 to 628, whereinX¹³ is selected from E and Q.

Aspect 632. The IL-2Rα ligand of any one of aspects 592 to 628, whereinX¹³ is E.

Aspect 633. The IL-2Rα ligand of any one of aspects 592 to 632, whereinX¹⁴ is C.

Aspect 634. The IL-2Rα ligand of any one of aspects 592 to 633, whereinX¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 635. The IL-2Rα ligand of any one of aspects 592 to 633, whereinX¹⁵ is selected from M, I, V, L, and F.

Aspect 636. The IL-2Rα ligand of any one of aspects 592 to 633, whereinX¹⁵ is selected from I and V.

Aspect 637. The IL-2Rα ligand of any one of aspects 592 to 636, whereinX¹⁶ is F.

Aspect 638. The IL-2Rα ligand of aspect 592, wherein X³ is C, X⁵ is L,X⁸ is P, X⁹ is G,

X¹² is W, X¹¹ is E, X¹⁴ is C, and X¹⁶ is F.

Aspect 639. The IL-2Rα ligand of aspect 592, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from N, Q, S, T, and Y;

X⁵ is L;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from N, Q, S, T, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, G, P, S, and T;

X¹² is W;

X¹³ is selected from E and Q;

X¹⁴ is C;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is F.

Aspect 640. The IL-2Rα ligand of aspect 592, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 178to SEQ ID NO: 195:

SEQ ID NO: 178 Q R C Q L S W S G G E L G C M F SEQ ID NO: 179A G C M L L K P G L Y W E C I F SEQ ID NO: 180A R C S L H H T G S R Y E C I F SEQ ID NO: 181A T C M L R L L G D G W G C V F SEQ ID NO: 182G P C R L S N P G T G W E C I F SEQ ID NO: 183K G C T L Q N P G S G W V C L F SEQ ID NO: 184L A C I L S K P G E H W E C L F SEQ ID NO: 185N G C T L S F S G M S W T C V Y SEQ ID NO: 186N S C I L S N P G L G W Q C V F SEQ ID NO: 187N T C K L F R S G N I W Q C I F SEQ ID NO: 188P S C R L W N P G F G W E C I F SEQ ID NO: 189Q S C T L Q R L G H L Y Q C W F SEQ ID NO: 190S A C T P N W T G R W W E C V F SEQ ID NO: 191S K C H L I V S G K F H E C V F SEQ ID NO: 192S S C T L F N P G T G W T C V F SEQ ID NO: 193S T C R M G N P G G V W G C Y F SEQ ID NO: 194T H C L V Q W P G P V V A C R S SEQ ID NO: 195T R C R L L K L G S L W E C F G

Aspect 641. The IL-2Rα ligand of any one of aspects 592 to 640, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 642. The IL-2Rα ligand of any one of aspects 640 to 641, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 643. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (16a) (SEQ IDNO: 196), or the amino acid sequence of Formula (16b) (SEQ ID NO: 197):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (16a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (16b)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is C;    -   X³ is selected from an amino acid comprising a basic side chain;    -   X⁴ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁵ is selected from an amino acid comprising a basic side chain        or a polar/neutral side chain;    -   X⁶ is selected from an amino acid comprising a basic side chain        or a polar/neutral side chain;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X¹³ is selected from an amino acid comprising an acidic side        chain;    -   X¹⁴ is C; and    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 644. The IL-2Rα ligand of aspect 643, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from C;

X³ is selected from H, K, and R;

X⁴ is selected from F, I, L, M, V, W, and Y;

X⁵ is selected from H, K, N, Q, R, S, T, and Y;

X⁶ is selected from H, K, N, Q, R, S, T, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from F, H, I, L, M, V, W, and Y;

X¹³ is selected from D and E;

X¹⁴ is C; and

X¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 645. The IL-2Rα ligand of any one of aspects 643 to 644, whereinX¹ is selected from A, K, N, R, and T.

Aspect 646. The IL-2Rα ligand of any one of aspects 643 to 645, whereinX² is C.

Aspect 647. The IL-2Rα ligand of any one of aspects 643 to 646, whereinX³ is selected from W, R, and T.

Aspect 648. The IL-2Rα ligand of any one of aspects 643 to 647, whereinX⁴ is selected from R, L, and V.

Aspect 649. The IL-2Rα ligand of any one of aspects 643 to 648, whereinX⁵ is selected from S, R, Q, K, and H.

Aspect 650. The IL-2Rα ligand of any one of aspects 643 to 649, whereinX⁶ is selected from W, Q, H, K, F, and R.

Aspect 651. The IL-2Rα ligand of any one of aspects 643 to 650, whereinX⁷ is selected from R, M, L, A, D, S, and I.

Aspect 652. The IL-2Rα ligand of any one of aspects 643 to 651, whereinX⁸ is selected from Y, S, P, G, and A.

Aspect 653. The IL-2Rα ligand of any one of aspects 643 to 652, whereinX⁹ is selected from P, R, Y, G, Q, P, and L.

Aspect 654. The IL-2Rα ligand of any one of aspects 643 to 653, whereinX¹⁰ is selected from T, G, P, N, T, N, and A.

Aspect 655. The IL-2Rα ligand of any one of aspects 643 to 654, whereinX¹¹ is selected from R, G, F, T, G, S, and E.

Aspect 656. The IL-2Rα ligand of any one of aspects 643 to 655, whereinX¹² is selected from T and W.

Aspect 657. The IL-2Rα ligand of any one of aspects 643 to 656, whereinX¹³ is selected from F, E, and S.

Aspect 658. The IL-2Rα ligand of any one of aspects 643 to 657, whereinX¹⁴ is C.

Aspect 659. The IL-2Rα ligand of any one of aspects 643 to 658, whereinX¹⁵ is selected from S, L, N, I, and V.

Aspect 660. The IL-2Rα ligand of any one of aspects 643 to 659, whereinX² is C.

Aspect 661. The IL-2Rα ligand of any one of aspects 643 to 660, whereinX³ is R.

Aspect 662. The IL-2Rα ligand of any one of aspects 643 to 661, whereinX⁴ is selected from L and V.

Aspect 663. The IL-2Rα ligand of any one of aspects 643 to 662, whereinX⁵ is selected from R, K, and H.

Aspect 664. The IL-2Rα ligand of any one of aspects 643 to 663, whereinX⁶ is selected from R, K, and H.

Aspect 665. The IL-2Rα ligand of any one of aspects 643 to 664, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 666. The IL-2Rα ligand of any one of aspects 643 to 665, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 667. The IL-2Rα ligand of any one of aspects 643 to 665, whereinX⁸ is G.

Aspect 668. The IL-2Rα ligand of any one of aspects 643 to 667, whereinX⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 669. The IL-2Rα ligand of any one of aspects 643 to 668, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 670. The IL-2Rα ligand of any one of aspects 643 to 669, whereinX¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 671. The IL-2Rα ligand of any one of aspects 643 to 670, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 672. The IL-2Rα ligand of any one of aspects 643 to 670, whereinX¹² is selected from F, W, and Y.

Aspect 673. The IL-2Rα ligand of any one of aspects 643 to 670, whereinX¹² is W.

Aspect 674. The IL-2Rα ligand of any one of aspects 643 to 673, whereinX¹³ is E.

Aspect 675. The IL-2Rα ligand of any one of aspects 643 to 674, whereinX¹⁴ is C.

Aspect 676. The IL-2Rα ligand of any one of aspects 643 to 675, whereinX¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 677. The IL-2Rα ligand of any one of aspects 643 to 675, whereinX¹⁵ is selected from L, I, and V.

Aspect 678. The IL-2Rα ligand of aspect 643, wherein X² is C, X³ is R,X¹² is W, X¹³ is E, and X¹⁴ is C.

Aspect 679. The IL-2Rα ligand of aspect 643, wherein,

X² is C;

X³ is R;

X⁴ is selected from F, I, L, M, V, W, and Y;

X⁵ is selected from N, Q, S, T, and Y;

X⁶ is selected from N, Q, S, T, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, G, P, S, and T;

X⁹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is W;

X¹³ is E;

X¹⁴ is C; and

X¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 680. The IL-2Rα ligand of aspect 643, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 198to SEQ ID NO: 204:

SEQ ID NO: 198 A C W R S W R Y P T R T F C S SEQ ID NO: 199K C R L R Q M S R G G W E C L SEQ ID NO: 200N C R V R H L P Y P F W S C L SEQ ID NO: 201R C R L Q K A G G N T W E C I SEQ ID NO: 202R C T L R F D A Q T G W E C N SEQ ID NO: 203T C R L K R S G P N S W E C I SEQ ID NO: 204T C T V H R I G L A E W E C V

Aspect 681. The IL-2Rα ligand of any one of aspects 643 to 680, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 682. The IL-2Rα ligand of any one of aspects 680 to 681, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 683. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (17a) (SEQ IDNO: 205), the amino acid sequence of Formula (17b) (SEQ ID NO: 206), orthe amino acid sequence of Formula (17c) (SEQ ID NO: 207):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (17a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (17b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C X¹⁵—X¹⁶—  (17c)

wherein,

-   -   X¹ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X² is selected from an amino acid comprising a basic side chain;    -   X³ is C;    -   X⁴ is selected from an amino acid comprising a basic side chain;    -   X⁵ is selected from an amino acid comprising a basic side chain        or an aromatic side chain or a large hydrophobic side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid;    -   X⁸ is P;    -   X⁹ is G;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid;    -   X¹³ is selected from an amino acid;    -   X¹⁴ is C;    -   X¹⁵ is selected from an amino acid comprising a large        hydrophobic side chain; and    -   X¹⁶ is selected from an amino acid comprising a small        hydrophobic side chain.

Aspect 684. The IL-2Rα ligand of aspect 683, wherein,

X¹ is selected from F, I, L, M, V, W, and Y;

X² is selected from H, K, and R;

X³ is C;

X⁴ is selected from H, K, and R;

X⁵ is selected from F, H, I, K, L, M, R, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁴ is C;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 685. The IL-2Rα ligand of any one of aspects 683 to 684, whereinX¹ is V.

Aspect 686. The IL-2Rα ligand of any one of aspects 683 to 685, whereinX² is selected from K, R, T, and Y.

Aspect 687. The IL-2Rα ligand of any one of aspects 683 to 686, whereinX³ is C.

Aspect 688. The IL-2Rα ligand of any one of aspects 683 to 687, whereinX⁴ is selected from K, F, R, and Y.

Aspect 689. The IL-2Rα ligand of any one of aspects 683 to 688, whereinX⁵ is selected from L, M, V, and R.

Aspect 690. The IL-2Rα ligand of any one of aspects 683 to 689, whereinX⁶ is selected from V, S, A, L, and E.

Aspect 691. The IL-2Rα ligand of any one of aspects 683 to 690, whereinX⁷ is selected from M, E, R, Y, V, and K.

Aspect 692. The IL-2Rα ligand of any one of aspects 683 to 691, whereinX⁸ is P.

Aspect 693. The IL-2Rα ligand of any one of aspects 683 to 692, whereinX⁹ is G.

Aspect 694. The IL-2Rα ligand of any one of aspects 683 to 693, whereinX¹⁰ is selected from S, R, L, Q, V, and G.

Aspect 695. The IL-2Rα ligand of any one of aspects 683 to 694, whereinX¹¹ is selected from G, V, T, M, and E.

Aspect 696. The IL-2Rα ligand of any one of aspects 683 to 695, whereinX¹² is selected from W, S, W, A, and M.

Aspect 697. The IL-2Rα ligand of any one of aspects 683 to 696, whereinX¹³ is selected from A, Y, E, V, and H.

Aspect 698. The IL-2Rα ligand of any one of aspects 683 to 697, whereinX¹⁴ is C.

Aspect 699. The IL-2Rα ligand of any one of aspects 683 to 697, whereinX¹⁴ is selected from H, T, L, V, F, and R.

Aspect 700. The IL-2Rα ligand of any one of aspects 683 to 697, whereinX¹⁴ is selected from F, A, and S.

Aspect 701. The IL-2Rα ligand of any one of aspects 683 to 700, whereinX¹ is V.

Aspect 702. The IL-2Rα ligand of any one of aspects 683 to 701, whereinX² is R.

Aspect 703. The IL-2Rα ligand of any one of aspects 683 to 702, whereinX³ is C.

Aspect 704. The IL-2Rα ligand of any one of aspects 683 to 703, whereinX⁴ is R.

Aspect 705. The IL-2Rα ligand of any one of aspects 683 to 704, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 706. The IL-2Rα ligand of any one of aspects 683 to 704, whereinX⁵ is selected from F, W, and Y.

Aspect 707. The IL-2Rα ligand of any one of aspects 683 to 704, whereinX⁵ is selected from H, K, and R.

Aspect 708. The IL-2Rα ligand of any one of aspects 683 to 707, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 709. The IL-2Rα ligand of any one of aspects 683 to 708, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 710. The IL-2Rα ligand of any one of aspects 683 to 709, whereinX⁸ is P.

Aspect 711. The IL-2Rα ligand of any one of aspects 683 to 710, whereinX⁹ is G.

Aspect 712. The IL-2Rα ligand of any one of aspects 683 to 711, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 713. The IL-2Rα ligand of any one of aspects 683 to 712, whereinX¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 714. The IL-2Rα ligand of any one of aspects 683 to 713, whereinX¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 715. The IL-2Rα ligand of any one of aspects 683 to 714, whereinX¹³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 716. The IL-2Rα ligand of any one of aspects 683 to 715, whereinX¹⁴ is C.

Aspect 717. The IL-2Rα ligand of any one of aspects 683 to 716, whereinX¹⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 718. The IL-2Rα ligand of any one of aspects 683 to 717, whereinX¹⁶ is S.

Aspect 719. The IL-2Rα ligand of aspect 683, wherein X¹ is V, X², is R,X³ is C, X⁴ is R, X¹⁴ is C, and X¹⁶ is S.

Aspect 720. The IL-2Rα ligand of aspect 683, wherein,

X¹ is V;

X² is R;

X³ is C;

X⁴ is R;

X⁵ is selected from H, F, I, K, L, M, R, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹⁴ is C;

X¹⁵ is selected from F, I, L, M, V, W, and Y; and

X¹⁶ is S.

Aspect 721. The IL-2Rα ligand of aspect 683, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 208to SEQ ID NO: 213:

SEQ ID NO: 208 V K C K L V N P G S G W A C H F SEQ ID NO: 209V R C F M S E P G R V S Y C T A SEQ ID NO: 210V R C R L A R P G L T W E C L S SEQ ID NO: 211V R C R V L Y P G Q M A V C V S SEQ ID NO: 212V T C Y R A V P G V E A Y C F S SEQ ID NO: 213V Y C R R E K P G G E M H C R S

Aspect 722. The IL-2Rα ligand of any one of aspects 683 to 721, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 723. The IL-2Rα ligand of any one of aspects 721 to 722, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 724. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (18a) (SEQ IDNO: 214), the amino acid sequence of Formula (18b) (SEQ ID NO: 215), orthe amino acid sequence of Formula (18c) (SEQ ID NO: 216):

—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—  (18a)

—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—  (18b)

—X¹—X²—C—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—C—X¹⁵—X¹⁶—  (18c)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is selected from an amino acid;    -   X³ is C;    -   X⁴ is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid;    -   X⁷ is selected from an amino acid;    -   X⁸ is P;    -   X⁹ is G;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid;    -   X¹³ is selected from an amino acid comprising an aromatic side        chain or a large hydrophobic side chain;    -   X¹⁴ is C;    -   X¹⁵ is selected from an amino acid; and    -   X¹⁶ is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 725. The IL-2Rα ligand of aspect 724, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from F, H, I, L, M, V, W, and Y;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is selected from F, H, I, L, M, V, W, and Y;

X¹⁴ is C;

X¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 726. The IL-2Rα ligand of any one of aspects 724 to 725, whereinX¹ is selected from A, H, Q, R, T, and V.

Aspect 727. The IL-2Rα ligand of any one of aspects 724 to 726, whereinX² is selected from T, G, L, D, and K.

Aspect 728. The IL-2Rα ligand of any one of aspects 724 to 727, whereinX³ is C.

Aspect 729. The IL-2Rα ligand of any one of aspects 724 to 728, whereinX⁴ is selected from H, T, P, A, F, Q, and Y.

Aspect 730. The IL-2Rα ligand of any one of aspects 724 to 729, whereinX⁵ is selected from L, W, G, I, E, M, and R.

Aspect 731. The IL-2Rα ligand of any one of aspects 724 to 730, whereinX⁶ is selected from L, T, S, M, and N.

Aspect 732. The IL-2Rα ligand of any one of aspects 724 to 731, whereinX⁷ is selected from A, K, D, E, W, T, and S.

Aspect 733. The IL-2Rα ligand of any one of aspects 724 to 732, whereinX⁸ is P.

Aspect 734. The IL-2Rα ligand of any one of aspects 724 to 733, whereinX⁹ is G.

Aspect 735. The IL-2Rα ligand of any one of aspects 724 to 734, whereinX¹⁰ is selected from V, A, S, T, D, Q, and V.

Aspect 736. The IL-2Rα ligand of any one of aspects 724 to 735, whereinX¹¹ is selected from D, E, W, S, R, and I.

Aspect 737. The IL-2Rα ligand of any one of aspects 724 to 736, whereinX¹² is selected from N, W, G, V, P, and A.

Aspect 738. The IL-2Rα ligand of any one of aspects 724 to 737, whereinX¹³ is selected from T, V, P, F, Y, and W.

Aspect 739. The IL-2Rα ligand of any one of aspects 724 to 738, whereinX¹⁴ is C.

Aspect 740. The IL-2Rα ligand of any one of aspects 724 to 738, whereinX¹⁴ is selected from I, S, P, D, H, T, and V.

Aspect 741. The IL-2Rα ligand of any one of aspects 724 to 738, whereinX¹⁴ is selected from F, L, N, I, T, and G.

Aspect 742. The IL-2Rα ligand of any one of aspects 724 to 741, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 743. The IL-2Rα ligand of any one of aspects 724 to 742, whereinX² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 744. The IL-2Rα ligand of any one of aspects 724 to 743, whereinX³ is C.

Aspect 745. The IL-2Rα ligand of any one of aspects 724 to 744, whereinX⁴ is selected from F, H, I, L, M, V, W, and Y.

Aspect 746. The IL-2Rα ligand of any one of aspects 724 to 744, whereinX⁴ is selected from F, W, and Y.

Aspect 747. The IL-2Rα ligand of any one of aspects 724 to 746, whereinX⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 748. The IL-2Rα ligand of any one of aspects 724 to 747, whereinX⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 749. The IL-2Rα ligand of any one of aspects 724 to 748, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 750. The IL-2Rα ligand of any one of aspects 724 to 749, whereinX⁸ is P.

Aspect 751. The IL-2Rα ligand of any one of aspects 724 to 750, whereinX⁹ is G.

Aspect 752. The IL-2Rα ligand of any one of aspects 724 to 751, whereinX¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 753. The IL-2Rα ligand of any one of aspects 724 to 752, whereinX¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 754. The IL-2Rα ligand of any one of aspects 724 to 753, whereinX¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 755. The IL-2Rα ligand of any one of aspects 724 to 754, whereinX¹³ is selected from F, H, I, L, M, V, W, and Y.

Aspect 756. The IL-2Rα ligand of any one of aspects 724 to 754, whereinX¹³ is selected from F, W, and Y.

Aspect 757. The IL-2Rα ligand of any one of aspects 724 to 756, whereinX¹⁴ is C.

Aspect 758. The IL-2Rα ligand of any one of aspects 724 to 757, whereinX¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 759. The IL-2Rα ligand of any one of aspects 724 to 758, whereinX¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 760. The IL-2Rα ligand of aspect 724, wherein X³ is C, X⁸ is P,X⁹ is G, and X¹⁴ is C.

Aspect 761. The IL-2Rα ligand of aspect 724, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X³ is C;

X⁴ is selected from F, H, W, and Y;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is P;

X⁹ is G;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is selected from F, H, W, and Y;

X¹⁴ is C;

X¹⁵ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; and

X¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 762. The IL-2Rα ligand of aspect 724, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 217to SEQ ID NO: 224:

SEQ ID NO: 217 A T C H L L A P G V D N T C I F SEQ ID NO: 218H G C T L T K P G A E W V C S F SEQ ID NO: 219Q L C P W S D P G S W G P C P L SEQ ID NO: 220R D C A G M E P G T S V F C D N SEQ ID NO: 221R D C F I L E P G T S V Y C D L SEQ ID NO: 222T D C Q E T W P G D R P W C H I SEQ ID NO: 223V K C F M S T P G Q I A Y C T T SEQ ID NO: 224V K C Y R N S P G V E A Y C V G

Aspect 763. The IL-2Rα ligand of any one of aspects 724 to 762, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 764. The IL-2Rα ligand of any one of aspects 762 to 763, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 765. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (19a) (SEQ IDNO: 225), or the amino acid sequence of Formula (19b) (SEQ ID NO: 226):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (19a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (19b)

wherein,

-   -   X¹ is selected from an amino acid;    -   X² is C;    -   X³ is selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X⁴ is selected from an amino acid comprising an acidic side        chain or a polar/neutral side chain;    -   X⁵ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X⁶ is selected from an amino acid comprising a polar/neutral        side chain;    -   X⁷ is selected from an amino acid;    -   X⁸ is selected from an amino acid;    -   X⁹ is selected from an amino acid comprising a large hydrophobic        side chain;    -   X¹⁰ is selected from an amino acid;    -   X¹¹ is selected from an amino acid;    -   X¹² is selected from an amino acid;    -   X¹³ is C; and    -   X¹⁴ is selected from an amino acid.

Aspect 766. The IL-2Rα ligand of aspect 765, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is C;

X³ is selected from D, E, N, Q, S, T, and Y;

X⁴ is selected from D, E, N, Q, S, T, and Y;

X⁵ is selected from F, I, L, M, V, W, and Y;

X⁶ is selected from N, Q, S, T, and Y;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from F, I, L, M, V, W, and Y;

X¹⁰ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X¹³ is C; and

X¹⁴ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 767. The IL-2Rα ligand of any one of aspects 765 to 766, whereinX¹ is selected from D, P, S, T, W, and Y.

Aspect 768. The IL-2Rα ligand of any one of aspects 765 to 767, whereinX² is C.

Aspect 769. The IL-2Rα ligand of any one of aspects 765 to 768, whereinX³ is selected from L, Q, M, E, W, and H.

Aspect 770. The IL-2Rα ligand of any one of aspects 765 to 769, whereinX⁴ is selected from D, R, S, E, and L.

Aspect 771. The IL-2Rα ligand of any one of aspects 765 to 770, whereinX⁵ is selected from L, P, F, and V.

Aspect 772. The IL-2Rα ligand of any one of aspects 765 to 771, whereinX⁶ is selected from R, A, K, H, and W.

Aspect 773. The IL-2Rα ligand of any one of aspects 765 to 772, whereinX⁷ is selected from G, E, K, R, D, G, and Q.

Aspect 774. The IL-2Rα ligand of any one of aspects 765 to 773, whereinX⁸ is selected from T, Y, S, M, Q, and D.

Aspect 775. The IL-2Rα ligand of any one of aspects 765 to 774, whereinX⁹ is selected from V, Y, and D.

Aspect 776. The IL-2Rα ligand of any one of aspects 765 to 775, whereinX¹⁰ is selected from G, S, E, N, and Y.

Aspect 777. The IL-2Rα ligand of any one of aspects 765 to 776, whereinX¹¹ is selected from M, Q, W, V, E, N, R, L, and M.

Aspect 778. The IL-2Rα ligand of any one of aspects 765 to 777, whereinX¹² is selected from V, Q, W, V, E, N, R, L, and M.

Aspect 779. The IL-2Rα ligand of any one of aspects 765 to 778, whereinX¹³ is C.

Aspect 780. The IL-2Rα ligand of any one of aspects 765 to 779, whereinX¹⁴ is selected from Q, L, D, N, I, P, and F.

Aspect 781. The IL-2Rα ligand of any one of aspects 765 to 780, whereinX¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 782. The IL-2Rα ligand of any one of aspects 765 to 781, whereinX² is C.

Aspect 783. The IL-2Rα ligand of any one of aspects 765 to 782, whereinX³ is selected from H, N, Q, S, T, and Y.

Aspect 784. The IL-2Rα ligand of any one of aspects 765 to 783, whereinX³ is selected from D and E.

Aspect 785. The IL-2Rα ligand of any one of aspects 765 to 783, whereinX³ is selected from Q and E.

Aspect 786. The IL-2Rα ligand of any one of aspects 765 to 785, whereinX⁴ is selected from D and E.

Aspect 787. The IL-2Rα ligand of any one of aspects 765 to 786, whereinX⁵ is L.

Aspect 788. The IL-2Rα ligand of any one of aspects 765 to 787, whereinX⁶ is selected from R, H, and K.

Aspect 789. The IL-2Rα ligand of any one of aspects 765 to 788, whereinX⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 790. The IL-2Rα ligand of any one of aspects 765 to 789, whereinX⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 791. The IL-2Rα ligand of any one of aspects 765 to 790, whereinX⁹ is Y.

Aspect 792. The IL-2Rα ligand of any one of aspects 765 to 791, whereinX¹⁰ is selected from A, G, P, S, and T.

Aspect 793. The IL-2Rα ligand of any one of aspects 765 to 792, whereinX¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y.

Aspect 794. The IL-2Rα ligand of any one of aspects 765 to 793, whereinX¹² is selected from F, I, L, M, V, W, and Y.

Aspect 795. The IL-2Rα ligand of any one of aspects 765 to 793, whereinX¹² is selected from V, L, and M.

Aspect 796. The IL-2Rα ligand of any one of aspects 765 to 795, whereinX¹³ is C.

Aspect 797. The IL-2Rα ligand of any one of aspects 765 to 796, whereinX¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 798. The IL-2Rα ligand of any one of aspects 765 to 796, whereinX¹⁴ is selected from F, I, and L.

Aspect 799. The IL-2Rα ligand of any one of aspects 765 to 766, whereinX² is C, X⁵ is L, and X¹ is C.

Aspect 800. The IL-2Rα ligand of aspect 765, wherein,

X¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X² is C;

X³ is selected from D, E, N, Q, S, T, and Y;

X⁴ is selected from D, E, N, Q, S, T, and Y;

X⁵ is L;

X⁶ is selected from A, G, H, K, P, S, and T;

X⁷ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁸ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y;

X⁹ is selected from F, I, L, M, V, W, and Y;

X¹⁰ is selected from A, G, P, S, and T;

X¹¹ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; and

X¹² is selected from F, I, L, M, V, W, and Y;

X¹³ is C; and

X¹⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 801. The IL-2Rα ligand of aspect 765, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 227to SEQ ID NO: 234:

SEQ ID NO: 227 D C L D L R G T V G M V C Q

SEQ ID NO: 228 P C Q R L A E Y Y S Q Q C L

SEQ ID NO: 229 S C M D L K G S V G W V C D

SEQ ID NO: 230 T C E S L A K M Y E V E C N

SEQ ID NO: 231 T C E S L A R M Y N E N C I

SEQ ID NO: 232 W C W E P H D Q Y Y V R C P

SEQ ID NO: 233 Y C H D F K G T V G T L C I

SEQ ID NO: 234 G C Q L V W Q D D S Y M C F Y

Aspect 802. The IL-2Rα ligand of any one of aspects 765 to 801, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 803. The IL-2Rα ligand of any one of aspects 801 to 802, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 804. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises the amino acid sequence of Formula (20a) (SEQ IDNO: 235), or the amino acid sequence of Formula (20b) (SEQ ID NO: 236):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—  (20a)

—X¹—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—C—X¹⁴—  (20b)

wherein,

-   -   X¹ is W;    -   X² is C;    -   X³ is selected from F, I, L, M, V, W, and Y;    -   X⁴ is G;    -   X⁵ is Q;    -   X⁶ is P;    -   X⁷ is L;    -   X⁸ is selected from F, I, L, M, V, W, and Y;    -   X⁹ is R;    -   X¹⁰ is selected from H, N, Q, F, I, L, M, V, W, and Y;    -   X¹¹ is G;    -   X¹² is S;    -   X¹³ is C; and    -   X¹⁴ is K.

Aspect 805. The IL-2Rα ligand of aspect 804, wherein X³ is selected fromI and V.

Aspect 806. The IL-2Rα ligand of any one of aspects 804 to 805, whereinX⁸ is selected from F and Y.

Aspect 807. The IL-2Rα ligand of any one of aspects 804 to 806, whereinX¹⁰ is selected from F, I, L, M, N, Q, S, T, V, W, and Y.

Aspect 808. The IL-2Rα ligand of any one of aspects 804 to 807, whereinX¹⁰ is selected from L and Q.

Aspect 809. The IL-2Rα ligand of aspect 804, wherein X¹ is W, X² is C,X⁴ is G, X⁵ is Q,

X⁶ is P, X⁷ is L, X⁹ is R, X¹¹ is G, X¹² is 5S, X¹¹ is C, and X¹⁴ is K.

Aspect 810. The IL-2Rα ligand of aspect 804, wherein,

X¹ is W;

X² is C;

X³ is selected from I and V;

X⁴ is G;

X⁵ is Q;

X⁶ is P;

X⁷ is L;

X⁸ can be selected from F and Y;

X⁹ is R;

X¹⁰ is selected from F, H, I, L, M, N, Q, S, T, V, W, and Y;

X¹¹ is G;

X¹² is S;

X¹³ is C; and

X¹⁴ is K.

Aspect 811. The IL-2Rα ligand of aspect 804, wherein the IL-2Rα ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 237to SEQ ID NO: 307:

SEQ ID NO: 237 W C I G Q P L F R Q G S C K SEQ ID NO: 238W C V G Q P L Y R L G S C K SEQ ID NO: 239 W D Q F Q L G W E A G V A ASEQ ID NO: 240 F L P W P V Y F S Q V L G G G SEQ ID NO: 241Y V M C S A F G C K S I SEQ ID NO: 242 H V I C S V N G G C R GSEQ ID NO: 243 I R F C L R S E P T A C W I V SEQ ID NO: 244I R C R Y E K Q S G I C L F SEQ ID NO: 245 G G C S L V W A D S W V C I FSEQ ID NO: 246 G C S L M W Q D G W W V C I SEQ ID NO: 247E W E C R F L P G R R G C S L F SEQ ID NO: 248K G C T L Q N P G S G W V C L F SEQ ID NO: 249T C R L K R S G P N S W E C I SEQ ID NO: 250 W C I G Q P L F R Q G S C KSEQ ID NO: 251 A V S C N S W R C I P W SEQ ID NO: 252A V C C D G N S C R R C SEQ ID NO: 253 F V H C S L M G C W C GSEQ ID NO: 254 R C L D L G G S V G L V C F SEQ ID NO: 255V C F N F R G T V G R H C W SEQ ID NO: 256V R C R Q N E P G G A Y W C S S SEQ ID NO: 257C V L R E G A E G W E C V W R SEQ ID NO: 258 C R M M Q G T Y G W T C L FSEQ ID NO: 259 C I L N D T I Q G W V C I Y SEQ ID NO: 260C T L Y R S A P G V W L C I F SEQ ID NO: 261 C L V F D Q Y G N Y K R R CSEQ ID NO: 262 I V C C N M F G C H T C R N SEQ ID NO: 263Q V C C T S R G C R V C A P V SEQ ID NO: 264 R V C C S M V G C R S C N LSEQ ID NO: 265 R V C C T F A G C R V C H K SEQ ID NO: 266R V C C T S D G C R G C R Q SEQ ID NO: 267 T V C C T V Q G C W P C S RSEQ ID NO: 268 V C C H Q T F G C Y R C K Q SEQ ID NO: 269C V V C S A L G C R A C V P R SEQ ID NO: 270V W D C F V R G W E V A A V A V G E SEQ ID NO: 271L T C L I F K P G T H R H C P V SEQ ID NO: 272R Y C S P L I P G S A L G C P R SEQ ID NO: 273I R C R L D P P G S Y K T C V F SEQ ID NO: 274R G V I C N H A G C R I W Y G SEQ ID NO: 275 T T Q S C T L R Y C W L L QSEQ ID NO: 276 W W I S C L R D L R C L E Y F SEQ ID NO: 277R H A C K T W Y R M C I V S SEQ ID NO: 278 A V S C S R L T G R C H S LSEQ ID NO: 279 W V A C N R V T G S C R P I SEQ ID NO: 280S H G V C C T Q S S C R S C R SEQ ID NO: 281 W V A C N R L S G C C R P ISEQ ID NO: 282 H T V C C Q D W G C R S C S G SEQ ID NO: 283M A C C T P R G C R P C SEQ ID NO: 284 R S V C C S S Y G C R A C F GSEQ ID NO: 285 C K L T C T S S T C S C V F SEQ ID NO: 286C M L K C T N A I C E C I F SEQ ID NO: 287 C R V W C N Q A E C M C I FSEQ ID NO: 288 S R C S F D V T K Q E C V F SEQ ID NO: 289L E C Q P Y R G P L Y Y C Q D SEQ ID NO: 290 S I C C T P Q L C H S C D GSEQ ID NO: 291 T T C C T S E G C H K C I T L SEQ ID NO: 292C V A C S S D G C S P I I C SEQ ID NO: 293 A I C S E D E G G E L C C W HSEQ ID NO: 294 H E I C C G P P G C H S C S V T SEQ ID NO: 295L S V C S C P P G Q L Y C M V E SEQ ID NO: 296S T W C C L H P G V G E C Q A V SEQ ID NO: 297V T Q C F D G P G S F R C C Y Q SEQ ID NO: 298R Q C N C L S P G E L V N C Q Q SEQ ID NO: 299M V S C T D L G C V V V G G G SEQ ID NO: 300V V H C L Q S G C Y S V G S G SEQ ID NO: 301T I K C G S S G W C W V E A G SEQ ID NO: 302M V S C T D L G C V V V G G G SEQ ID NO: 303H E I C C G P P G C H S C S V T SEQ ID NO: 304L S V C S C P P G Q L Y C M V E SEQ ID NO: 305S T W C C L H P G V G E C Q A V SEQ ID NO: 306V T Q C F D G P G S F R C C Y Q SEQ ID NO: 307R Q C N C L S P G E L V N C Q Q

Aspect 812. The IL-2Rα ligand of any one of aspects 804 to 811, wherein,

the amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini;

the amino acid sequence comprises a truncated amino acid sequence; or

the amino acid sequence comprises a truncated amino acid sequence,wherein the truncated amino acid sequence independently comprises from 1to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 813. The IL-2Rα ligand of any one of aspects 811 to 812, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 814. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 400 to SEQ ID NO: 423:

SEQ ID NO: 400 W D D F I L G W E A G V A A V G E V SEQ ID NO: 401F L P W P V Y F S Q V L G G R R SEQ ID NO: 402Y V M C S A F G C K S I G G SEQ ID NO: 403 H V I C S V N G G C R G G GSEQ ID NO: 404 G G I R F C L R S E P T A C W I V G G SEQ ID NO: 405G G I R C R Y E K Q S G I C L F G G SEQ ID NO: 423G G G G C S L V W A D S W V C I F G G SEQ ID NO: 406G G G C S L M W Q D G W W V C I G G SEQ ID NO: 407G G E W E C R F L P G R R G C S L F G G SEQ ID NO: 408G G K G C T L Q N P G S G W V C L F G G SEQ ID NO: 409G G T C R L K R S G P N S W E C I G G SEQ ID NO: 410G G W C I G Q P L F R Q G S C K G G SEQ ID NO: 411F V L C G L Q G C R S G G SEQ ID NO: 412 F V P W D E Y F L Q I L G GSEQ ID NO: 413 G G G W V I C S A L G C P F G G SEQ ID NO: 414G G G R R F C L R S E P T A C W T V G G SEQ ID NO: 415G G G S R C S L V W A D S W V C I F G G SEQ ID NO: 416G G D W E C L F L P G R R G C T L F G G SEQ ID NO: 417F I P W D E Y F A Q L L G G SEQ ID NO: 418 F V P W D V Y F S Q I L G GSEQ ID NO: 419 F I P W D E Y F K Q V L G G SEQ ID NO: 420F V P W P E Y F L Q I M G G SEQ ID NO: 421 F I P W E E Y F S Q L L G GSEQ ID NO: 422 F I P W P E Y F S Q L L G G

Aspect 815. The IL-2Rα ligand of aspect 814, wherein the amino acidsequence comprises a truncated amino acid sequence.

Aspect 816. The IL-2Rα ligand of any one of aspects 814 to 815, whereinthe amino acid sequence independently comprises from 1 to 4 glycines (G)(SEQ ID NO: 1041) on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 817. The IL-2Rα ligand of any one of aspects 814 to 816, whereinfrom 1 to 5 of the amino acids is independently substituted with anotheramino acid.

Aspect 818. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.

Aspect 819. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises an amino acid sequence having greater than 70%,greater than 75%, greater than 80%, greater than 85%, greater than 90%,or greater than 95% sequence similarity to any one of SEQ ID NO: 1 toSEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.

Aspect 820. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises a truncated amino acid sequence of any one ofSEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.

Aspect 821. The IL-2Rα ligand of any one of aspects 1 to 6, wherein theIL-2Rα ligand comprises an amino acid sequence having greater than 70%,greater than 75%, greater than 80%, greater than 85%, greater than 90%,or greater than 95% sequence similarity to a truncated amino acidsequence of any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID NO. 400to SEQ ID NO: 423.

Aspect 822. A compound comprising an IL-2Rα ligand of any one of aspects1 to 821.

Aspect 823. The compound of aspect 822, wherein the compound is selectedfrom a peptide, a conjugate, a fusion protein, and a single chain tandempeptide.

Aspect 825. The compound of aspect 823, wherein the compound is apeptide.

Aspect 825. The compound of aspect 824, wherein the peptide has amolecular weight within a range from 500 Daltons to 15,000 Daltons.

Aspect 826. The compound of any one of aspects 825 to 826, wherein thepeptide comprises from 5 amino acids to 4,000 amino acids.

Aspect 827. The compound of aspect 823, wherein the compound comprises aconjugate.

Aspect 828. The compound of aspect 827, wherein the conjugate comprisesat least one IL-2Rα ligand.

Aspect 829. The compound of aspect 827, wherein the conjugate comprises:at least two IL-2Rα ligands; and at least one linker attached to each ofthe at least two IL-2Rα ligands.

Aspect 830. The compound of any one of aspects 823 to 829, wherein theconjugate comprises at least one IL-2Rβ ligand and/or at least oneIL-2Rγc ligand.

Aspect 831. The compound of any one of aspects 823 to 829, wherein theconjugate comprises: at least two IL-2Rβ ligands; and at least onelinker attached to each of the at least two IL-2Rβ ligands.

Aspect 832. The compound of aspect 823, wherein the conjugate comprises:at least two IL-2Rγc ligands; and at least one linker attached to eachof the at least two IL-2Rγc ligands.

Aspect 833. The compound of aspect 823, wherein the conjugate comprises:at least one IL-2Rβ ligand; at least one IL-2Rγc ligand; and at leastone linker attached to the at least one IL-2Rβ ligand and to the atleast one IL-2Rγc ligand.

Aspect 834. The compound of any one of aspects 823 to 833, wherein theconjugate comprises at least one moiety, amino acid, or polypeptideconfigured to modify a property of the conjugate.

Aspect 835. The compound of aspect 834, wherein the property is selectedfrom aqueous solubility, polarity, lipophilicity, pharmacokineticprofile, targeting, bioavailability, pH-dependent binding, bioactivity,pharmacodynamics, cellular activity, metabolism, therapeutic efficacy,and caging (reversible incapacitation).

Aspect 836. The compound of any one of aspects 834 to 835, wherein theat least one moiety is cleavable in vivo.

Aspect 837. The compound of any one of aspects 834 to 836, wherein theat least one moiety comprises an irreversibly cleavable promoiety.

Aspect 838. The compound of aspect 837, wherein the promoiety isconfigured to be releasable in a target-specific environment.

Aspect 839. The compound of aspect 838, wherein the target-specificenvironment comprises an enzyme, pH, or a combination thereof.

Aspect 840. The compound of any one of aspects 834 to 839, wherein themoiety comprises a small molecule, polymer, a peptide, or an antibody.

Aspect 841. The compound of any one of aspects 834 to 840, wherein themoiety comprises a pharmacokinetic moiety.

Aspect 842. The compound of aspect 841, wherein the pharmacokineticmoiety comprises a polyethylene glycol.

Aspect 843. The compound of any one of aspects 834 to 842, wherein themoiety comprises a tumor-targeting moiety.

Aspect 844. The compound of aspect 843, wherein the tumor-targetingmoiety comprises a tumor-specific antibody, a tumor-specific antibodyfragment, a tumor-specific protein, or a tumor-specific peptide.

Aspect 845. The compound of any one of aspects 834 to 844, wherein themoiety comprises an immune cell-targeting moiety.

Aspect 846. The compound of any one of aspects 822 to 845, wherein thecompound comprises a linker covalently bound to the IL-2Rα ligand.

Aspect 847. The compound of aspect 846, wherein the linker is selectedfrom a peptide having from 2 amino acids to 200 amino acids.

Aspect 848. The compound of any one of aspects 846 to 847, wherein thelinker comprises a polyethylene glycol.

Aspect 849. The compound of any one of aspects 822 to 848, wherein thecompound comprises a heteromer, wherein the heteromer comprises:

an IL-2Rα ligand;

an IL-2Rβ ligand;

an IL-2Rγc ligand; and

a linker;

wherein each of the IL-2Rα ligand, the IL-2Rβ ligand and the IL-2Rγcligand comprise an amino-terminus (N-terminus), a carboxy terminus(C-terminus), and an amino acid side chain;

wherein the IL-2Rα ligand is bonded to the linker through theamino-terminus (N-terminus), the carboxy terminus (C-terminus), an aminoacid side chain, or a combination of any of the foregoing; and

wherein the IL-2Rβ ligand is bonded to the linker through theamino-terminus (N-terminus), the carboxy terminus (C-terminus), an aminoacid side chain, or a combination of any of the foregoing; and

wherein the IL-2Rγc ligand is bonded to the linker through theamino-terminus (N-terminus), the carboxy terminus (C-terminus), an aminoacid side chain, or a combination of any of the foregoing.

Aspect 850. The compound of any one of aspects 822 to 848, wherein thecompound comprises a heteromer, wherein the heteromer comprises:

an IL-2Rα ligand;

an IL-2Rβ ligand;

an IL-2Rγc ligand; and

a linker;

wherein each of the IL-2Rα ligand, the IL-2Rβ ligand, and the IL-2Rγcligand comprises an amino-terminus (N-terminus) and a carboxy terminus(C-terminus); and

wherein each of the IL-2Rα ligand, the IL-2Rβ ligand, and the IL-2Rγcligand is covalently bound to the linker.

Aspect 851. The compound of aspect 850, wherein each of the IL-2Rαligand, the IL-2Rβ ligand, and the IL-2Rγc ligand is covalently bound tothe linker through the respective C-terminus and/or through therespective N-terminus.

Aspect 852. The compound of aspect 850, wherein,

the IL-2Rα ligand is covalently bound to the linker through an aminoacid side chain;

the IL-2Rβ ligand is covalently bound to the linker through an aminoacid side chain; and/or

the IL-2Rγc ligand is covalently bound to the linker through an aminoacid side chain.

Aspect 853. The compound of aspect 850, wherein,

the IL-2Rα ligand is covalently bound to the linker through an aminoacid side chain, through the C-terminus, or through the N-terminus;

the IL-2Rβ ligand is covalently bound to the linker through an aminoacid side chain, through the C-terminus, or through the N-terminus; and

the IL-2Rγc ligand is covalently bound to the linker through an aminoacid side chain, through the C-terminus, or through the N-terminus.

Aspect 854. The compound of any one of aspects 850 to 853, wherein theheteromer is configured to activate the IL-2 receptor.

Aspect 855. The compound of any one of aspects 850 to 853, wherein thelinker is configured such that the heteromer activates the IL-2receptor.

Aspect 856. The compound of any one of aspects 822 to 855, wherein thecompound is an IL-2R agonist.

Aspect 857. The compound of any one of aspects 822 to 855, wherein thecompound is an IL-2R antagonist.

Aspect 858. The compound of any one of aspects 822 to 855, wherein thecompound comprises a conformation configured to activate human IL-2Rβγcsignaling pathways.

Aspect 859. The compound of any one of aspects 822 to 858, wherein thecompound comprises a single chain peptide.

Aspect 860. The compound of aspect 859, wherein the single chain peptidecomprises at least one IL-2Rβ ligand.

Aspect 861. The compound of any one of aspects 859 to 860, wherein thesingle chain peptide comprises: at least two IL-2Rβ ligands; and atleast one linker attached to the at least two IL-2Rβ ligands.

Aspect 862. The compound of any one of aspects 859 to 861, wherein thesingle chain peptide comprises a least one IL-2Rγc ligand.

Aspect 863. The compound of any one of aspects 859 to 862, wherein thesingle chain peptide comprises: at least two IL-2Rγc ligands; and atleast one linker attached to the at least two IL-2Rγc ligands.

Aspect 864. The compound of any one of aspects 859 to 863, wherein thesingle chain tandem peptide comprises:

at least one IL-2Rα ligand;

at least one IL-2Rβ ligand;

at least one IL-2Rγc ligand; and

at least one linker attached to the at least one IL-2Rα ligand, to theat least one IL-2Rβ ligand, and to the at least one IL-2Rγc ligand.

Aspect 865. The compound of any one of aspects 822 to 864, wherein thecompound is a fusion protein.

Aspect 866. The compound of aspect 865, wherein the fusion proteincomprises:

at least one IL-2Rα ligand;

at least one IL-2Rβ ligand;

at least one IL-2Rγc ligand; and

a peptide linker domain, wherein the peptide linker domain is bound tothe at least one IL-2Rα ligand, to the at least one IL-2Rβ ligand, andto the at least one IL-2Rγc ligand.

Aspect 867. The compound of aspect 865, wherein,

each peptide linker domain has an amino-terminus (N-terminus) and acarboxy terminus (C-terminus); and

the C-terminus of the IL-2Rα ligand is fused through a peptide bond tothe N-terminus of the peptide linker domain, and the C-terminus of thepeptide linker domain is fused to a protein fusion partner.

Aspect 868. The compound of aspect 867, wherein the protein fusionpartner comprises an IgG molecule, an IgG Fab fragment, or an Fcfragment,

Aspect 868. The compound of any one of aspects 867 to 868, wherein theprotein fusion partner comprises IL-2, a variant of IL-2, a mutant ofIL-2, or an IL-2R agonist.

Aspect 870. The compound of aspect 865, wherein,

each peptide linker domain has an amino-terminus (N-terminus) and acarboxy terminus (C-terminus); and

the N-terminus of the IL-2Rα ligand is fused through a peptide bond tothe C-terminus of the peptide linker domain, and the N-terminus of thepeptide linker domain is fused to a protein fusion partner.

Aspect 871. The compound of aspect 870 wherein the protein fusionpartner comprises an IgG molecule, an IgG Fab fragment, or an Fcfragment,

Aspect 872. The compound of any one of aspects 870 to 871, wherein theprotein fusion partner comprises IL-2, a variant of IL-2, a mutant ofIL-2, or an IL-2R agonist.

Aspect 873. A nucleic acid encoding the fusion protein of aspect 865.

Aspect 874. The compound of any one of aspects 822 to 872, wherein thecompound comprises a label.

Aspect 875. The compound of aspect 874, wherein the label is selectedfrom a radioisotope, a fluorophore, or a combination thereof.

Aspect 876. The compound of any one of aspects 822 to 875, wherein thecompound comprises a cage to protect peripheral tissues for the toxicityof IL-2R activation.

Aspect 877. The compound of any one of aspects 822 to 876, wherein thecompound comprises a promoiety.

Aspect 878. The compound of aspect 877, wherein the promoiety comprisesa moiety configured to sustain a circulating reservoir of the compound.

Aspect 879. The compound of any one of aspects 822 to 878, wherein thecompound comprises a moiety configured to target IL-2R-directedimmuno-stimulation of the effector immune cells in the tumor.

Aspect 880. The compound of any one of aspects 822 to 879, wherein thecompound comprises a cleavable moiety.

Aspect 881. The compound of aspect 880, wherein the cleavable moiety iscleavable by electromagnetic radiation, thermal energy, pH, or acombination of any of the foregoing.

Aspect 882. The compound of any one of aspects 822 to 881, wherein thecompound comprises a moiety that is toxic to cells having high IL-2Rαexpression.

Aspect 883. The compound of aspect 882, wherein the cells having highIL-2Rα expression are Treg cells.

Aspect 884. The compound of aspect 882, wherein the toxic moiety is acleavable moiety.

Aspect 885. The compound of aspect 884, the cleavable moiety iscleavable by electromagnetic radiation, thermal energy, pH, or acombination of any of the foregoing.

Aspect 886. The compound of any one of aspects 882 to 885, wherein thetoxic moiety is activated by electromagnetic radiation, thermal energy,pH, or a combination of any of the foregoing.

Aspect 887. The compound of any one of aspects 822 to 886, wherein thecompound comprises an imaging agent, a diagnostic agent, a targetingagent, a therapeutic agent, or a combination of any of the foregoing.

Aspect 888. A pharmaceutical composition comprising;

the IL-2Rα ligand of any one of aspects 1 to 821;

a compound of any one of aspects 822 to 887; or

a combination of any of the foregoing.

Aspect 889. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of the pharmaceutical composition of aspect 880.

Aspect 890. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of;

the IL-2Rα ligand of any one of aspects 1 to 821;

the compound of any one of aspects 822 to 887; or

a combination of any of the foregoing.

Aspect 891. The method of any one of aspects 889 and 890, wherein thecancer comprises a solid tumor.

Aspect 892. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of the pharmaceutical composition ofaspect 888.

Aspect 893. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of;

the IL-2Rα ligand of any one of aspects 1 to 821;

the compound of any one of aspects 822 to 887; or

a combination of any of the foregoing.

Aspect 894. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of the pharmaceutical composition ofaspect 888.

Aspect 895. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of;

the IL-2Rα ligand of any one of aspects 1 to 821;

the compound of any one of aspects 822 to 8887; or

a combination of any of the foregoing.

Aspect 896. A method of screening compounds for IL-2α activity,comprising:

contacting a cell with,

-   -   the IL-2Rα ligand of any one of aspects 1 to 821;    -   the compound of any one of aspects 822 to 887; or    -   a combination of any of the foregoing.    -   wherein the cell expresses the IL-2α subunit; and

contacting the cell with a test compound; and

determining the activity of the test compound.

Aspect 897. A method of activating the human IL-2 receptor, comprisingcontacting a cell expressing the human IL-2 receptor in vivo with theIL-2Rα ligand of any one of aspects 1 to 821 or a compound comprisingthe IL-2Rα ligand of any one of aspects 1 to 821.

Aspect 898. A method of activating the human IL-2 receptor in a patient,comprising administering to a patient an effective amount of the IL-2Rαligand of any one of aspects 1 to 821 or a compound comprising theIL-2Rα ligand of any one of aspects 1 to 821.

Aspect 899. A method of treating a disease in a patient, wherein theIL-2 receptor signaling pathway is associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of the IL-2Rα ligand of any one ofaspects 1 to 821 or a compound comprising the IL-2Rα ligand of any oneof aspects 1 to 821.

Aspect 900. A method of treating a disease in a patient, whereinactivation of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of the IL-2Rα ligand of any one ofaspects 1 to 821 or a compound comprising the IL-2Rα ligand of any oneof aspects 1 to 821.

Aspect 901. A method of treating a disease in a patient, whereininhibition of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount the IL-2Rα ligand of any one of aspects1 to 821 or of a compound comprising the IL-2Rα ligand of any one ofaspects 1 to 821.

Aspect 902. A method of treating a disease in a patient, wherein cellsexpressing the IL-2Rα subunit (CD25) are associated with the etiology ofthe disease, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the IL-2Rα ligand of anyone of aspects 1 to 821 or a compound comprising the IL-2Rα ligand ofany one of aspects 1 to 821.

Aspect 903. A method of treating a disease in a patient, wherein bindingto the IL-2Rα subunit (CD25) is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount the IL-2Rα ligand of any one of aspects1 to 821 or of a compound comprising the IL-2Rα ligand of any one ofaspects 1 to 821.

Aspect 904. A method of treating a disease in a patient, whereininhibiting binding of an IL-2R agonist to the IL-2Rα subunit (CD25) iseffective in treating the disease, comprising administering to a patientin need of such treatment a therapeutically effective amount of theIL-2Rα ligand of any one of aspects 1 to 821 or a compound comprisingthe IL-2Rα ligand of any one of aspects 1 to 821.

Aspect 905. A method of treating a disease in a patient, whereinreducing the sensitivity of Treg cells to IL-2 is effective in treatingthe disease, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the IL-2Rα ligand of anyone of aspects 1 to 821 or a compound comprising the IL-2Rα ligand ofany one of aspects 1 to 821.

Aspect 906. A method of treating a disease in a patient, whereininhibiting binding to the IL-2Rα subunit (CD25) is effective in treatingthe disease, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the IL-2Rα ligand of anyone of aspects 1 to 821 or a compound comprising the IL-2Rα ligand ofany one of aspects 1 to 821.

Aspect 907. A method of treating a disease in a patient, wherein theetiology of the disease is associated with activation of Treg cells,comprising administering to a patient in need of such treatment atherapeutically effective amount of the IL-2Rα ligand of any one ofaspects 1 to 821 or a compound comprising the IL-2Rα ligand of any oneof aspects 1 to 821.

Aspect 908. A method of treating a disease in a patient, wherein theetiology of the disease is associated with cells exhibiting a highIL-2Rα expression, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the IL-2Rα ligand of anyone of aspects 1 to 821 or a compound comprising the IL-2Rα ligand ofany one of aspects 1 to 821.

Aspect 909. A method of imaging cells expressing the IL-2Rα subunitcomprising administering to a patient an effective amount of the IL-2Rαligand of any one of aspects 1 to 821 or a compound comprising theIL-2Rα ligand of any one of aspects 1 to 821.

Aspect 910. A method of diagnosing a disease in a patient wherein thedisease is associated with cells expressing the IL-2Rα subunitcomprising administering to a patient an effective amount of the IL-2Rαligand of any one of aspects 1 to 821 or a compound comprising theIL-2Rα ligand of any one of aspects 1 to 821.

Aspect 911. A method of targeting a compound to cells expressing theIL-2Rα subunit comprising administering to a patient an effective amountof the IL-2Rα ligand of any one of aspects 1 to 821 or a compoundcomprising the IL-2Rα ligand of any one of aspects 1 to 821.

Aspect 912. A method of delivering a cytotoxic compound to cellsexpressing the IL-2Rα subunit comprising administering to a patient aneffective amount of the IL-2Rα ligand of any one of aspects 1 to 821 ora compound comprising a cytotoxic moiety and the IL-2Rα ligand of anyone of aspects 1 to 821.

Aspect 913. The method of any one of aspects 897 to 912, wherein thecompound comprises the compound of any one of aspects 822 to 887.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein but maybe modified within the scope and equivalents thereof.

What is claimed is:
 1. An IL-2Rα ligand, wherein, the IL-2Rα ligand bindto the human IL-2Rα subunit with an IC₅₀ of less than 100 μM; and theIL-2Rα ligand comprises an amino acid sequence selected from any one ofSEQ ID NOS: 4, 9, 24, 31, 44, 50, 67, 79, 100, 112, 135, 144, 154, 172,180, 203, 210, 219, 234, 250, and 418: SEQ ID NO: 4F L H W P V Y F C Q V M SEQ ID NO: 9 F I P W D E Y F K Q V LSEQ ID NO: 24 F V H C T L L G C W S G SEQ ID NO: 31W V I C S A V G C R P F SEQ ID NO: 44 H V I C S V N G G C R GSEQ ID NO: 50 E Q F C L V S D P M A C W S L SEQ ID NO: 67R R F C L R S E P A A C W F V SEQ ID NO: 79 S K C V Y D Y N F G T C I FSEQ ID NO: 100 S L N C K T R P G L R W C T W T SEQ ID NO: 112A W E C L F L P G H R G C S L F SEQ ID NO: 135R Q F C L V S P G Y E D C W F V SEQ ID NO: 144S A C Q L K W D E G W T C L F SEQ ID NO: 154R G C S L V W S G S W E C I F SEQ ID NO: 172 G C T L S W N Q G W W H C VSEQ ID NO: 180 A R C S L H H T G S R Y E C I F SEQ ID NO: 203T C R L K R S G P N S W E C I SEQ ID NO: 210V R C R L A R P G L T W E C L S SEQ ID NO: 219Q L C P W S D P G S W G P C P L SEQ ID NO: 234G C Q L V W Q D D S Y M C F Y SEQ ID NO: 250 W C I G Q P L F R Q G S C KSEQ ID NO: 418 F V P W D V Y F S Q I L G G


2. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprises theamino acid sequence of SEQ ID NO:
 4. 3. The IL-2Rα ligand of claim 1,wherein the IL-2Rα ligand comprises the amino acid sequence of SEQ IDNO:
 9. 4. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligandcomprises the amino acid sequence of SEQ ID NO:
 24. 5. The IL-2Rα ligandof claim 1, wherein the IL-2Rα ligand comprises the amino acid sequenceof SEQ ID NO:
 31. 6. The IL-2Rα ligand of claim 1, wherein the IL-2Rαligand comprises the amino acid sequence of SEQ ID NO:
 44. 7. The IL-2Rαligand of claim 1, wherein the IL-2Rα ligand comprises the amino acidsequence of SEQ ID NO:
 50. 8. The IL-2Rα ligand of claim 1, wherein theIL-2Rα ligand comprises the amino acid sequence of SEQ ID NO:
 67. 9. TheIL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprises the aminoacid sequence of SEQ ID NO:
 79. 10. The IL-2Rα ligand of claim 1,wherein the IL-2Rα ligand comprises the amino acid sequence of SEQ IDNO:
 100. 11. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligandcomprises the amino acid sequence of SEQ ID NO:
 112. 12. The IL-2Rαligand of claim 1, wherein the IL-2Rα ligand comprises the amino acidsequence of SEQ ID NO:
 135. 13. The IL-2Rα ligand of claim 1, whereinthe IL-2Rα ligand comprises the amino acid sequence of SEQ ID NO: 144.14. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprisesthe amino acid sequence of SEQ ID NO:
 154. 15. The IL-2Rα ligand ofclaim 1, wherein the IL-2Rα ligand comprises the amino acid sequence ofSEQ ID NO:
 172. 16. The IL-2Rα ligand of claim 1, wherein the IL-2Rαligand comprises the amino acid sequence of SEQ ID NO:
 180. 17. TheIL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprises the aminoacid sequence of SEQ ID NO:
 203. 18. The IL-2Rα ligand of claim 1,wherein the IL-2Rα ligand comprises the amino acid sequence of SEQ IDNO:
 210. 19. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligandcomprises the amino acid sequence of SEQ ID NO:
 219. 20. The IL-2Rαligand of claim 1, wherein the IL-2Rα ligand comprises the amino acidsequence of SEQ ID NO:
 234. 21. The IL-2Rα ligand of claim 1, whereinthe IL-2Rα ligand comprises the amino acid sequence of SEQ ID. NO: 250.22. The IL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprisesthe amino acid sequence of SEQ ID. NO:
 418. 23. The IL-2Rα ligand ofclaim 1, wherein the IL-2Rα ligand has a greater than 70% sequencesimilarity to any one of SEQ ID NOS: 4, 9, 24, 31, 44, 50, 67, 79, 100,112, 135, 144, 154, 172, 180, 203, 210, 219, 234, 250, and
 418. 24. TheIL-2Rα ligand of claim 1, wherein the IL-2Rα ligand comprises atruncated IL-2Rα ligand of any one of SEQ ID NOS: 4, 9, 24, 31, 44, 50,67, 79, 100, 112, 135, 144, 154, 172, 180, 203, 210, 219, 234, 250, and418, in which from 1 to 3 amino acids is removed from the N-terminus,the C-terminus, or from both the N-terminus and the C-terminus.
 25. Acompound comprising at least one IL-2Rα ligand of claim
 1. 26. Thecompound of claim 25, wherein the compound is selected from a peptide, aconjugate, and a fusion protein.
 27. A pharmaceutical compositioncomprising the IL-2Rα ligand of claim
 1. 28. A pharmaceuticalcomposition comprising the compound of claim 26.